Macrocycles and their uses

ABSTRACT

The present application describes organic compounds that are useful for the treatment, prevention and/or amelioration of diseases.

BACKGROUND

Since the discovery of penicillin, pharmaceutical companies haveproduced a number of antibacterial agents to combat a wide variety ofbacterial infections. In the past several years, there has been rapidemergence of bacterial resistance to several of these antibiotics. Themultidrug resistance among these bacterial pathogens may also be due tomutation leading to more virulent clinical isolation. Perhaps the mostdisturbing occurrence has been the acquisition of resistance tovancomycin, an antibiotic generally regarded as the agent of last resortfor serious Gram-positive infections.

This is true especially of some Gram-positive pathogen groups, such asstaphylococci, pneumococci and enterococci (S. Ewig et al.;Antibiotika-Resistenz bei Erregem ambulant erworbenerAtemwegsinfektionen (Antibiotic resistance in pathogens ofoutpatient-acquired respiratory tract infections); Chemother. J. 2002,11, 12-26; F. Tenover; Development and spread of bacterial resistance toantimicrobial agents: an overview; Clin. Infect. Dis. 2001 Sep. 15, 33Suppl. 3, 108-115) as well as Staphylococcus, Streptococcus,Mycobacterium, Enterococcus, Corynebacterium, Borrelia, Bacillus,Chlamydia, Mycoplasma, and the like.

A problem of equally large dimension is the increasing incidence of themore virulent, methicillin-resistant Staphylococcus aureas (MRSA) amongclinical isolates found worldwide. As with vancomycin resistantorganisms, many MRSA strains are resistant to most of the knownantibiotics, but MRSA strains have remained sensitive to vancomycin.However, in view of the increasing reports of vancomycin resistantclinical isolates and growing problem of bacterial resistance, there isan urgent need for new molecular entities effective against the emergingand currently problematic Gram-positive organisms.

This growing multidrug resistance has recently rekindled interest in thesearch for new structural classes of antibiotics that inhibit or killthese bacteria.

SUMMARY OF THE INVENTION

There remains a need for new treatments and therapies for bacterialinfections. There is also a need for compounds useful in the treatmentor prevention or amelioration of one or more symptoms of bacterialinfections. Furthermore, there is a need for methods for modulating theactivity of the elongation factor EF-Tu, using the compounds providedherein. In one aspect, the invention provides a compound of formula I:

In another aspect, the invention provides a compound of formula II:

In yet another aspect, the invention provides a compound of formula III:

In yet another aspect, the invention provides a compound of formula IV:

In another aspect, the invention provides a method of treating abacterial infection wherein the treatment includes administering to asubject in need thereof a pharmaceutically acceptable amount of acompound of formula I, II, III, or IV (or any subformula thereof), suchthat the bacterial infection is treated.

In another aspect, the invention provides a method of treating an EF-Tuassociated-state wherein the treatment includes administering to asubject in need thereof a pharmaceutically acceptable amount of acompound of formula I, II, III, or IV (or any subformula thereof), suchthat the EF-Tu associated state is treated.

In still another aspect, the invention provides a method of treating,inhibiting or preventing the activity of EF-Tu in a subject in needthereof, which includes administering to the subject a pharmaceuticallyacceptable amount of a compound of formula I, II, III, or IV (or anysubformula thereof). In one embodiment, a bacterial infection is treatedin a subject in need thereof.

In another aspect, the invention provides a method of treating,inhibiting or preventing the activity of bacteria in a subject in needthereof, which includes administering to the subject a pharmaceuticallyacceptable amount of a compound of formula I, II, III, or IV (or anysubformula thereof), wherein the compound interacts with any target inthe life cycle of the bacteria. In one embodiment, the target is EF-Tu.

In another aspect, the invention provides a method of treating abacterial infection in a subject, wherein the treatment includesadministering to a subject in need thereof a pharmaceutically acceptableamount of a compound of the formula I, II, III, or IV (or any subformulathereof), and a pharmaceutically acceptable carrier, such that thebacterial infection is treated.

In still another aspect, the invention provides a method of treating abacterial infection wherein the treatment includes administering to asubject in need thereof a pharmaceutically effective amount of acompound of the formula I, II, III, or IV (or any subformula thereof),in combination with a pharmaceutically effective amount of an additionaltherapeutic agent, such that the bacterial infection is treated. In oneembodiment, the compound of the formula I, II, III, or IV (or anysubformula thereof) and the other pharmaceutical agent are administeredas part of the same pharmaceutical composition. In another embodiment,the compound of the formula I, II, III, or IV (or any subformulathereof) and the other therapeutic agent are administered as separatepharmaceutical compositions, and the compound is administered prior to,at the same time as, or following administration of the other agent.

In another aspect, the invention provides a packaged bacterial infectiontreatment, comprised of formula I, II, III, or IV (or any subformulathereof), packaged with instructions for using an effective amount ofthe compound to treat a bacterial infection.

In another aspect, the invention provides a method of treating acne insubject in need thereof, wherein the treatment includes administering tothe subject a pharmaceutically acceptable amount of a compound offormula I, II, III, or IV (or any subformula thereof).

In yet another aspect, the invention provides a pharmaceuticalcomposition which includes a compound of formula I, II, III, or IV (orany subformula thereof), and at least one pharmaceutically acceptablecarrier or diluent.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to compounds, e.g., macrocyclic compounds,and intermediates thereto, as well as pharmaceutical compositionscontaining the compounds for use in treatment of bacterial infection.This invention is also directed to the compounds of the invention orcompositions thereof as modulators of the elongation factor EF-Tu. Thecompounds are particularly useful in interfering with the life cycle ofbacteria and in treating or preventing a bacterial infection orphysiological conditions associated therewith. The present invention isalso directed to methods of combination therapy for inhibiting EF-Tuactivity in cells, or for treating or preventing a bacterial infectionin patients using the compounds of the invention or pharmaceuticalcompositions, or kits thereof.

In one aspect, the invention provides compounds of the formula I:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including pyridine N-oxides thereof;

wherein

q is 0, 1, 2, or 3;

E is absent or a divalent residue selected from C(O), C(O)C(O), C(O)O,N(R₉), C(O)N(R₉), N(R₉)C(O), N(R₉)C(O)C(O), N(R₉)C(O)O, N(R₉)C(O)N(R₉),C(NR₉)N(R₉), N(R₉)C(NR₉), N(R₉)C(NR₉)N(R₉), S(O)_(m), S(O)_(m)N(R₉),N(R₉)S(O)_(m) and N(R₉)S(O)_(m)N(R₉);

R₁ is hydrogen or is selected from the group consisting of C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, C₁₋₈alkoxy, cycloalkylC₀₋₆alkyl,heterocycloalkylC₀₋₆alkyl, arylC₀₋₆alkyl, heteroarylC₀₋₆alkyl each ofwhich is substituted with 0 to 6 residues independently selected at eachoccurrence from the group consisting of hydroxy, oxo, C₁₋₈alkyl (whichmay be further substituted with 0-3 residues independently selected fromhydroxyl, halogen, amino, C₁₋₄alkoxy, COOH, CONH₂, or COOC₁₋₄alkyl),C₁₋₈alkoxy (which may be further substituted with 0-3 residuesindependently selected from hydroxyl, halogen, amino, C₁₋₄alkoxy, COOH,CONH₂, or COOC₁₋₄alkyl), C₃₋₇cycloalkylC₀₋₆alkyl (which may be furthersubstituted with 0-3 residues independently selected from hydroxyl,halogen, amino, C₁₋₄alkoxy, COOH, CONH₂, or COOC₁₋₄alkyl), COOH, NH₂,mono- and di-C₁₋₈alkylamino, tri-C₁₋₈alkylammonium, heterocycleC₀₋₆alkyl(which may be further substituted with 0-3 residues independentlyselected from hydroxyl, halogen, amino, C₁₋₄alkoxy, COOH, CONH₂, orCOOC₁₋₄alkyl), heteroarylC₀₋₆alkyl (which may be further substitutedwith 0-3 residues independently selected from hydroxyl, halogen, amino,C₁₋₄alkoxy, COOH, CONH₂, or COOC₁₋₄alkyl) and —(CH₂—CH₂—O—)_(n)—R₈;

R₂, R₃ and R₆ are each independently selected, at each occurrence fromthe group consisting of hydrogen, halogen, hydroxy, or oxo, or areindependently selected from the group consisting of C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, C₁₋₈alkoxy, amino, mono- anddi-C₁₋₈alkylamino, C₃₋₇cycloalkylC₀₋₆alkyl, heterocycloalkylC₀₋₆alkyl,arylC₀₋₆alkyl, or heteroarylC₀₋₆alkyl, each of which is substituted withhydroxy, oxo, halo, C₁₋₈alkyl, haloC₁₋₈alkyl, C₁₋₈alkoxy,haloC₁₋₈alkoxy, C₃₋₇cycloalkylC₀₋₆alkyl, COOH, NH₂, mono- anddi-C₁₋₈alkylamino, tri-C₁₋₈alkylammonium, heterocycleC₀₋₆alkyl,heteroarylC₀₋₆alkyl and —(CH₂—CH₂—O—)_(n)—R₈;

or R₂ and R₅, taken in combination, form a 4 to 7 membered heterocyclicring which is saturated or partially unsaturated and is furthersubstituted with 0-4 residues, each independently selected from R_(2a);

R₄ is hydrogen, oxo or NH or is selected from the group consisting ofCOOH, CONH₂, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl(CR₁₀R₁₁)_(q),heteroaryl(CR₁₀R₁₁)_(q), C₃₋₇cycloalkyl(CR₁₀R₁₁)_(q), each of which issubstituted with 0-3 R_(4a) residues;

R_(2a) and R_(4a) are each independently selected at each occurrencefrom hydrogen or from the group consisting of C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, C₁₋₈alkoxy, amino, mono- and di-C₁₋₈alkylamino,C₃₋₇cycloalkylC₀₋₆alkyl, C(O)(CH₂)_(z)R_(4b), C(O)N(H)(CH₂)_(z)R_(4b),or heterocycloalkylC₀₋₆alkyl, each of which is substituted with 0 to 4substituents independently selected at each occurrence from hydroxy,oxo, halo, C₁₋₈alkyl, haloC₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkoxy,C₃₋₇cycloalkylC₀₋₆alkyl, COOH, NH₂, mono- and di-C₁₋₈alkylamino,tri-C₁₋₈alkylammonium, heterocycleC₀₋₆alkyl, heteroarylC₀₋₆alkyl, or—(CH₂—CH₂—O—)_(n)—R₈;

R_(4b) is selected from the group consisting of H, OH, NH₂, C₁₋₈alkyl,C₁₋₈alkoxy, mono- and di-C₁₋₈alkylamino, heterocycle, cycloalkyl, and-E-R₁;

R₅ is independently selected at each occurrence from the groupconsisting of H, C₁₋₈alkyl, and —(CH₂—CH₂—O—)_(n)—R₈,

R₇ is selected from the group consisting of H, OH, NH₂, C₁₋₈alkyl,C₁₋₈alkoxy, mono- and di-C₁₋₈alkylamino, heterocycle, cycloalkyl, and-E-R₁;

R_(7a) is OR_(7b) or N(R_(7b))₂;

R_(7b) is independently selected, at each occurrence, from hydrogen orfrom the group consisting of C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl,C₁₋₈alkoxy, amino, mono- and di-C₁₋₈alkylamino, C₃₋₇cycloalkylC₀₋₆alkyl,heterocycloalkylC₀₋₆alkyl, arylC₀₋₆alkyl, or heteroarylC₀₋₆alkyl, eachof which is substituted with hydroxy, oxo, halo, C₁₋₈alkyl,haloC₁₋₈alkyl, C₁₋₈alkoxy, haloC₁₋₈alkoxy, C₃₋₇cycloalkylC₀₋₆alkyl,COOH, NH₂, mono- and di-C₁₋₈alkylamino, tri-C₁₋₈alkylammonium,heterocycleC₀₋₆alkyl, heteroarylC₀₋₆alkyl and —(CH₂—CH₂—O—)_(n)—R₈;

n is an integer of between 1-60,000 or is a mean of a plurality ofintegers having a value of between 1-60,000;

R₈ is independently selected at each occurrence from the groupconsisting of H, C₁₋₈alkyl and CH₂CO₂H;

R₉ is hydrogen or is selected from the group consisting of C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, C₁₋₈alkoxy, cycloalkylC₀₋₆alkyl,heterocycloalkylC₀₋₆alkyl, arylC₀₋₆alkyl, heteroarylC₀₋₆alkyl each ofwhich is substituted with 0 to 6 residues independently selected at eachoccurrence from the group consisting of hydroxy, oxo, C₁₋₈alkyl (whichmay be further substituted with 0-3 residues independently selected fromhydroxyl, halogen, amino, C₁₋₄alkoxy, COOH, CONH₂, or COOC₁₋₄alkyl),C₁₋₈alkoxy (which may be further substituted with 0-3 residuesindependently selected from hydroxyl, halogen, amino, C₁₋₄alkoxy, COOH,CONH₂, or COOC₁₋₄alkyl), C₃₋₇cycloalkylC₀₋₆alkyl (which may be furthersubstituted with 0-3 residues independently selected from hydroxyl,halogen, amino, C₁₋₄alkoxy, COOH, CONH₂, or COOC₁₋₄alkyl), COOH, NH₂,mono- and di-C₁₋₈alkylamino, tri-C₁₋₈alkylammonium, heterocycleC₀₋₆alkyl(which may be further substituted with 0-3 residues independentlyselected from hydroxyl, halogen, amino, C₁₋₄alkoxy, COOH, CONH₂, orCOOC₁₋₄alkyl), heteroarylC₀₋₆alkyl (which may be further substitutedwith 0-3 residues independently selected from hydroxyl, halogen, amino,C₁₋₄alkoxy, COOH, CONH₂, or COOC₁₋₄alkyl) and —(CH₂—CH₂—O—)_(n)—R₈;

q is 0, 1, 2, or 3;

z is an integer of from 0 to 6;

R₁₀ is absent, hydrogen, or C₁₋₈alkyl; and

R₁₁ is hydrogen, hydroxy, OR_(4a), C(O)R_(4a), C(O)OR_(4a),C(O)N(R_(4a))₂, OC(O)N(R_(4a))₂, oxo, amino, NHR_(4a), N(R_(4a))₂,═NR_(4a), C(NR_(4a))N(R_(4a))₂ or N(R_(4a))C(NR_(4a))N(R_(4a))₂.

In certain aspects, compounds of Formula I include those compounds inwhich each occurrence of R₅ is hydrogen. Certain other compounds ofFormula I include those compounds in which R₆ is independently selectedat each occurrence from the group consisting of H, halogen, C₁₋₈alkyl,C₁₋₈alkoxy, mono- and di-C₁₋₈alkylamino, heterocycle and—O—(CH₂—CH₂—O—)_(n)—R₈. In yet other compounds, R₆ is hydrogen ormethyl. Still other compounds of Formula I include those compounds inwhich R₇ and each occurrence of R_(7b) are hydrogen.

In other aspects, compounds of Formula I include those compounds inwhich q is 0, 1, or 2; and E is a divalent residue selected from C(O),C(O)C(O), C(O)O, N(R₉), C(O)N(R₉), N(R₉)C(O), N(R₉)C(O)C(O), N(R₉)C(O)O,N(R₉)C(O)N(R₉), S(O)₂, S(O)₂N(R₉), N(R₉)S(O)₂, and N(R₉)S(O)₂N(R₉) or Eis selected from the group consisting of C(O), C(O)C(O), C(O)O, N(H),C(O)N(H), N(H)C(O), N(H)C(O)C(O), N(H)C(O)O, N(H)C(O)N(H), S(O)₂,S(O)₂N(H), N(H)S(O)₂, and N(H)S(O)₂N(H). In certain other compounds ofFormula I, q is 0, 1 or 2 and E is a divalent residue selected fromC(O), C(O)O, N(R₉), C(O)N(R₉), N(R₉)C(O), N(R₉)C(O)O, andN(R₉)C(O)N(R₉).

In still other aspects, compounds of Formula I include those compoundsin which q is 0, 1, or 2; E is a divalent residue selected from N(R₉),C(O)N(R₉), N(R₉)C(O), N(R₉)C(O)O, N(R₉)C(O)N(R₉); and R₉ is selectedfrom hydrogen and C₁₋₈alkyl groups substituted by 0, 1, or 2 COOHgroups. In certain compounds of Formula I, q is 0; E is a divalentresidue selected from N(R₉), C(O)N(R₉), N(R₉)C(O), N(R₉)C(O)O,N(R₉)C(O)N(R₉); and R₉ is selected from hydrogen and C₁₋₈alkyl groupssubstituted by 0, 1, or 2 COOH groups.

In certain aspects, compounds of Formula I include those compounds inwhich R₁, and R₉ are independently selected at each occurrence from thegroup consisting of H, C₁₋₈alkyl, C₃₋₈cycloalkyl, and R₁₂, wherein theC₁₋₈alkyl and C₃₋₈cycloalkyl groups are unsubstituted or substitutedwith 1 or 2 groups selected from halogen, hydroxyl, or COOH.

In certain other aspects, compounds of Formula I include those compoundsin which the fragment:

is selected from groups in which q is 0, E is N(R₉), N(R₉)C(O), orN(R₉)C(O)O; R₉ is hydrogen or Z-CO₂H; R₁ is Z-CO₂H; and Z isC₁-C₈alkylene, C₃-C₈cycloalkylene, C₃-C₈heterocycloalkylene, phenylene,or 5-6 membered heteroarylene, each of which is optionally substitutedwith one or more groups independently selected from C₁-C₄alkyl,C₁-C₄alkoxy, hydroxy, amino, mono- and di-C₁-C₆alkylamino, C(O)OH, orhalogen.

In still other aspects, compounds of Formula I include those compoundsin which the fragment:

is selected from the group consisting of:

Certain other compounds of Formula I include those compounds in which qis 0; E-R₁ is selected from the group consisting of:

and R₁ is selected from the group consisting of hydrogen, hydroxymethyl,aminomethyl and R₁₂; and pharmaceutically acceptable salts thereof.

In yet other aspects, compounds of Formula I include those compounds inwhich q is 0; E-R₁ is selected from the group consisting of

and R₁, and R₉ are independently selected from the group consisting ofhydrogen, hydroxymethyl, aminomethyl and R₁₂; and pharmaceuticallyacceptable salts thereof.

Yet other compound of Formula I include those compounds in which R₂ isoxo or hydroxy or R₂ is selected from the group consisting of:

-   R_(2a) is selected from hydrogen, amino, hydroxy, or R₁₃; and-   p is 0, 1, 2, 3, or 4.

Still other compounds of Formula I include those compounds in which R₃is selected from

-   R_(3a), OR_(3a), N(R_(3a))₂ or R₁₃;-   p is 0, 1, 2, 3, or 4; and-   R_(3a) is independently selected, at each occurrence from hydrogen,    hydroxymethyl, aminomethyl or-   R₁₂; and pharmaceutically acceptable salts thereof.

Yet other compounds of Formula I include those compounds in which R₄ isselected from hydrogen, CO₂R_(4a), C(O)N(R_(4a))₂, N(R_(3a))₂, orC(R₁₀)(R₁₁)phenyl;

-   R₁₀ is absent or hydrogen;-   R₁₁ is hydrogen, oxo, R_(4a), OR_(4a), N(R_(4a))₂, or ═NR_(4a);-   R_(4a) is independently selected at each occurrence from hydrogen,    hydroxymethyl, aminomethyl and-   R₁₂; and pharmaceutically acceptable salts thereof.

Still other compounds of Formula I include those compounds in which R₇is selected from the group consisting of H, OH, NH₂, C₁₋₈alkyl,C₁₋₈alkoxy, and mono- and di-C₁₋₈alkylamino and R_(7b) is independentlyselected at each occurrence from hydrogen and C₁₋₄alkyl.

In other aspects, the invention provides compounds of Formula II:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including pyridine N-oxides thereof; wherein q is 1, or 2 and thefragment

is selected from the group consisting of:

-   q is 0 and E-R₁ is selected from the group consisting of:

-   R₁ is selected from the group consisting of hydrogen, hydroxymethyl,    and aminomethyl and R₁₂:-   R₂ is oxo or hydroxy or R₂ is selected from the group consisting of:

-   R_(2a) is selected from hydrogen, amino, hydroxy or R₁₃;-   R₃ is selected from R₁₂, OR₁₂, N(R₁₂)₂ or R₁₃;-   R₄ is selected from hydrogen, CO₂R_(4a), C(O)N(R_(4a))₂, OR_(3a),    N(R_(3a))₂, or C(R₁₀(R₁₁)phenyl;-   R_(4a) is independently selected at each occurrence from hydrogen,    hydroxymethyl, aminomethyl or R₁₂;    -   R₆ is hydrogen or C₁₋₄alkyl;    -   R₇ is selected from the group consisting of H, OH, NH₂,        C₁₋₈alkyl, C₁₋₈alkoxy, and mono- and di-C₁₋₈alkylamino;    -   R_(7a) is OR_(7b) or N(R_(7b))₂;    -   R_(7b) is independently selected at each occurrence from the        group consisting of H, C₁₋₈alkyl and —(CH₂—CH₂—O—)_(n)—R₈;-   R₈ is independently selected at each occurrence from the group    consisting of H, C₁₋₈alkyl and CH₂CO₂H;-   R₉ is selected from R₁₂;-   R₁₀ is absent or hydrogen; and-   R₁₁ is oxo, OR_(4a), N(R_(4a))₂, or ═NR_(4a); and pharmaceutically    acceptable salts thereof.

Certain other compounds of Formula I include those compounds representedby Formula III:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including pyridine N-oxides thereof; wherein q is 1, or 2 and thefragment

is selected from the group consisting of:

-   q is 0 and E-R₁ is selected from the group consisting of:

-   and R₁ is selected from the group consisting of hydrogen,    hydroxymethyl, and aminomethyl and R₁₂:    -   R_(2a) is hydrogen, hydroxy or amino, or is selected from the        group consisting of C₁₋₈alkoxy, amino, mono- and        di-C₁₋₈alkylamino, C₃₋₇cycloalkylC₀₋₆alkoxy, each of which is        substituted with hydroxy, oxo, halo, C₁₋₈alkyl, haloC₁₋₈alkyl,        C₁₋₈alkoxy, haloC₁₋₈alkoxy, C₃₋₇cycloalkylC₀₋₆alkyl, COOH, NH₂,        mono- and di-C₁₋₈alkylamino, tri-C₁₋₈alkylammonium,        heterocycleC₀₋₆alkyl, heteroarylC₀₋₆alkyl, or        —(CH₂—CH₂—O—)_(n)—R₈;-   R₃ is selected from R₁₂, OR₁₂, N(R₁₂)₂ or R₁₃;-   R₄ is selected from hydrogen, CO₂R_(4a), C(O)N(R_(4a))₂, OR_(3a),    N(R_(3a))₂, or C(R₁₀(R₁₁)phenyl;-   R_(4a) is independently selected at each occurrence from hydrogen,    hydroxymethyl, aminomethyl or R₁₂;    -   R₆ is hydrogen or C₁₋₄alkyl;    -   R₇ is selected from the group consisting of H, OH, NH₂,        C₁₋₈alkyl, C₁₋₈alkoxy, and mono- and di-C₁₋₈alkylamino;    -   R_(7a) is selected from the group consisting of H and C₁₋₈alkyl;        and-   R_(7b) is independently selected at each occurrence from the group    consisting of H, C₁₋₈alkyl and —(CH₂—CH₂—O—)_(n)—R₈, wherein R₈ is    independently selected at each occurrence from the group consisting    of H, C₁₋₈alkyl and CH₂CO₂H;-   R₉ is selected from R₁₂;-   R₁₀ is absent or hydrogen;-   R₁₁ is oxo OR_(4a), N(R_(4a))₂, or ═NR_(4a);-   n is an integer of between 1-60,000 or is a mean of a plurality of    integers having a value of between 1-60,000;-   p is 0, 1, 2, 3, or 4;-   and pharmaceutically acceptable salts thereof.

Certain compounds of Formula II or Formula III include those compoundsin which R₇ and each occurrence of R_(7b) are hydrogen.

In still other aspects, compounds of Formula II or Formula III includethose compounds in which the fragment:

is selected from the group consisting of:

In certain other aspects, compounds of Formula II and III include thosecompounds in which the fragment:

is selected from groups in which q is 0, E is N(R₉), N(R₉)C(O), orN(R₉)C(O)O; R₉ is hydrogen or Z-CO₂H; R₁ is Z-CO₂H; and Z isC₁-C₈alkylene, C₃-C₈cycloalkylene, C₃-C₈heterocycloalkylene, phenylene,or 5-6 membered heteroarylene, each of which is optionally substitutedwith one or more groups independently selected from C₁-C₄alkyl,C₁-C₄alkoxy, hydroxy, amino, mono- and di-C₁-C₆alkylamino, C(O)OH, orhalogen.

Certain other compounds of Formula II and III include those compounds inwhich q is 0; E-R₁ is selected from the group consisting of:

-   and R₁ is selected from the group consisting of hydrogen,    hydroxymethyl, aminomethyl and R₁₂; and pharmaceutically acceptable    salts thereof.

In yet other aspects, compounds of Formula Formula II and III includethose compounds in which q is 0; E-R₁ is selected from the groupconsisting of

-   and R₁ is selected from the group consisting of hydrogen,    hydroxymethyl, aminomethyl and R₁₂; and pharmaceutically acceptable    salts thereof.

Certain other compounds of Formula II or Formula III include thosecompounds in which q is 0; E-R₁ is selected from the group consistingof:

-   and R₁ is selected from the group consisting of hydrogen,    hydroxymethyl, aminomethyl and R₁₂; and pharmaceutically acceptable    salts thereof.

Yet other compound of Formula II or Formula III include those compoundsin which R₂ is oxo or hydroxy or R₂ is selected from the groupconsisting of:

-   R_(2a) is selected from hydrogen, amino, hydroxy, or R₁₃; and-   p is 0, 1, 2, 3, or 4.

Still other compounds of Formula II or Formula III include thosecompounds in which R₃ is selected from R_(3a), OR_(3a), N(R_(3a))₂ orR₁₃;

-   p is 0, 1, 2, 3, or 4; and-   R_(3a) is independently selected, at each occurrence from hydrogen,    hydroxymethyl, aminomethyl or-   R₁₂; and pharmaceutically acceptable salts thereof.

Yet other compounds of Formula II or Formula III include those compoundsin which R₄ is selected from hydrogen, CO₂R_(4a), C(O)N(R_(4a))₂,N(R_(4a))₂, or C(R₁₀)(R₁₁)phenyl;

-   R₁₀ is absent or hydrogen;-   R₁₁ is hydrogen, oxo, R_(4a), OR_(4a), N(R_(4a))₂, or ═NR_(4a);-   R_(4a) is independently selected at each occurrence from hydrogen,    hydroxymethyl, aminomethyl and-   R₁₂; and pharmaceutically acceptable salts thereof.

Still other compounds of Formula II or Formula III include thosecompounds in which R₇ is selected from the group consisting of H, OH,NH₂, C₁₋₈alkyl, C₁₋₈alkoxy, and mono- and di-C₁₋₈alkylamino and R_(7b)is independently selected at each occurrence from hydrogen andC₁₋₄alkyl. In other compounds R₇ is selected from the group consistingof H, OH, NH₂, C₁₋₈alkyl, C₁₋₈alkoxy, and mono- and di-C₁₋₈alkylamino;and R_(7a) and R_(7b) are hydrogen.

In certain aspects, the invention provides compounds represented byFormula IV:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including pyridine N-oxides thereof; wherein

E is selected from the group consisting of C(O), C(O)C(O), C(O)O, N(R₉),C(O)N(R₉), N(R₉)C(O), N(R₉)C(O)C(O), N(R₉)C(O)O, N(R₉)C(O)N(R₉), S(O)₂,S(O)₂N(R₉), N(R₉)S(O)₂, and N(R₉)S(O)₂N(R₉);

R₁ is hydrogen or is selected from the group consisting of C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, C₁₋₈alkoxy, cycloalkylC₀₋₆alkyl,heterocycloalkylC₀₋₆alkyl, arylC₀₋₆alkyl, heteroarylC₀₋₆alkyl each ofwhich is substituted with 0 to 6 residues independently selected at eachoccurrence from the group consisting of hydroxy, oxo, C₁₋₈alkyl,C₁₋₈alkoxy, C₃₋₇cycloalkylC₀₋₆alkyl, COOH, NH₂, mono- anddi-C₁₋₈alkylamino, tri-C₁₋₈alkylammonium, heterocycleC₀₋₆alkyl,heteroarylC₀₋₆alkyl and —(CH₂—CH₂—O—)_(n)—R₈;

R₈ is independently selected at each occurrence from the groupconsisting of H, C₁₋₈alkyl and CH₂CO₂H; and

R₉ is hydrogen or is selected from the group consisting of C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, C₁₋₈alkoxy, cycloalkylC₀₋₆alkyl,heterocycloalkylC₀₋₆alkyl, arylC₀₋₆alkyl, heteroarylC₀₋₆alkyl each ofwhich is substituted with 0 to 6 residues independently selected at eachoccurrence from the group consisting of hydroxy, oxo, C₁₋₈alkyl,C₁₋₈alkoxy, C₃₋₇cycloalkylC₀₋₆alkyl, COOH, NH₂, mono- anddi-C₁₋₈alkylamino, tri-C₁₋₈alkylammonium, heterocycleC₀₋₆alkyl,heteroarylC₀₋₆alkyl and —(CH₂—CH₂—O—)_(n)—R₈.

In certain aspects, compounds of Formula IV include those compounds inwhich R₁, and R₉ are independently selected at each occurrence from thegroup consisting of H, C₁₋₈alkyl, C₃₋₈cycloalkyl, and R₁₂, wherein theC₁₋₈alkyl and C₃₋₈cycloalkyl groups are unsubstituted or substitutedwith 1 or 2 groups selected from halogen, hydroxyl, or COOH.

In yet other aspects, compounds of Formula IV include those compounds inwhich E is N(R₉), N(R₉)C(O), or N(R₉)C(O)O; R₉ is hydrogen or Z-CO₂H; R₁is Z-CO₂H; and Z is C₁-C₈alkylene, C₃-C₈cycloalkylene,C₃-C₈heterocycloalkylene, phenylene, or 5-6 membered heteroarylene, eachof which is optionally substituted with one or more groups independentlyselected from C₁-C₄alkyl, C₁-C₄alkoxy, hydroxy, amino, mono- anddi-C₁-C₆alkylamino, C(O)OH, or halogen.

In still other aspects, compounds of Formula IV include those compoundsin which E-R₁ is selected from the group consisting of

and R₁, and R₉ are independently selected from the group consisting ofhydrogen, hydroxymethyl, aminomethyl and R₁₂; and pharmaceuticallyacceptable salts thereof.

In other aspects, compounds of Formula IV include those compounds inwhich E-R₁ is selected from the group consisting of

and R₁, and R₉ are independently selected from the group consisting ofhydrogen, hydroxymethyl, aminomethyl and R₁₂; and pharmaceuticallyacceptable salts thereof.

In certain compounds of Formula IV, R₁, and R₉ are selected from thegroup consisting of —(CH₂)_(n)CO₂H and C₄₋₇cycloalkyl-CO₂H, wherein s is2, 3, 4, 5 or 6.

R₁₂ in compounds of Formula I, Formula II, Formula III, Formula IV andsubformulae thereof is a residue independently selected at eachoccurrence from the group consisting of

-   n is an integer of between 1-60,000 or is a mean of a plurality of    integers having a value of between 1-60,000.

In certain compounds of Formula I, Formula II, Formula III, andsubformulae thereof, R₁₃ is independently selected at each occurrence,from the group consisting of

-   p is 0, 1, 2, 3, or 4.

Preferred embodiments of Formula I, II, III, IV or any subformulaethereof (including pharmaceutically acceptable salts thereof, as well asenantiomers, stereoisomers, rotamers, tautomers, diastereomers,atropisomers or racemates thereof, including N-pyridine-oxides thereof)include the compounds of Examples 1-143 infra, and are also consideredto be “compounds of the invention.” The compounds of the invention arealso referred to herein as “antibiotics” and “EF-Tu inhibitors.”

In certain embodiments, the compound of the present invention is furthercharacterized as a modulator of EF-Tu, including a prokaryotic EF-Tu,and especially including a bacterial EF-Tu. In a preferred embodiment,the compound of the invention is an EF-Tu inhibitor.

As used herein, the term “bacterial infection(s)” includes, but is notlimited to, bacterial infections that occur in mammals, fish and birdsas well as disorders related to bacterial infections that may be treatedor prevented by administering antibiotics such as the compounds of thepresent invention. In addition to treating infections caused bymulti-drug resistant strains of Staphyloccocus aureus, Streptococcuspneumoniae, Mycobacterium tuberculosis and Enterococci, the compounds ofthe present invention are useful in treating infections caused by otherbacteria including, but not limited to, Clostridium difficile,Propionibacterium acnes, Bacteroides fagiles, Neisseria gonorrhoeae,Branhamella catarrhalis, Haemophilus influenzae, E. coli, Pseudomonasaeruginosa, Proteus vulgaris, Klebsiella pneumonia, and Chlamydiatrachomatis.

Such bacterial infections and disorders related to such infectionsinclude, but are not limited to, the following: acne, rosacea, skininfection, pneumonia, otitis media, sinusitus, bronchitis, tonsillitis,and mastoiditis related to infection by Streptococcus pneumoniae,Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus,Peptostreptococcus spp. or Pseudomonas spp.; pharynigitis, rheumaticfever, and glomerulonephritis related to infection by Streptococcuspyogenes, Groups C and G streptococci, Clostridium diptheriae, orActinobacillus haemolyticum; respiratory tract infections related toinfection by Mycoplasma pneumoniae, Legionella pneumophila,Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydiapneumoniae; uncomplicated skin and soft tissue infections, abscesses andosteomyelitis, and puerperal fever related to infection byStaphylococcus aureus, coagulase-positive staphylococci (i.e., S.epidermidis, S. hemolyticus, etc.), S. pyogenes, S. agalactiae,Streptococcal groups C—F (minute-colony streptococci), viridansstreptococci, Corynebacterium spp., Clostridium spp., or Bartonellahenselae; uncomplicated acute urinary tract infections related toinfection by S. saprophyticus or Enterococcus spp.; urethritis andcervicitis; sexually transmitted diseases related to infection byChlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum,Ureaplasma urealyticum, or Nesseria gonorrheae; toxin diseases relatedto infection by S. aureus (food poisoning and Toxic shock syndrome), orGroups A, S, and C streptococci; ulcers related to infection byHelicobacter pylori; systemic febrile syndromes related to infection byBorrelia recurrentis; Lyme disease related to infection by Borreliaburgdorferi; conjunctivitis, keratitis, and dacrocystitis related toinfection by C. trachomatis, N. gonorrhoeae, S. aureus, S. pneumoniae,S. pyogenes, H. influenzae, or Listeria spp.; disseminated Mycobacteriumavium complex (MAC) disease related to infection by Mycobacterium avium,or Mycobacterium intracellulare; gastroenteritis related to infection byCampylobacter j ejuni; intestinal protozoa related to infection byCryptosporidium spp., odontogenic infection related to infection byviridans streptococci; persistent cough related to infection byBordetella pertussis; gas gangrene related to infection by Clostridiumperfringens or Bacteroides spp.; Skin infection by S. aureus,Propionibacterium acne; atherosclerosis related to infection byHelicobacter pylori or Chlamydia pneumoniae; or the like.

Further bacterial infections and disorders related to such infectionsthat may be treated or prevented in animals include, but are not limitedto, the following: bovine respiratory disease related to infection by P.haemolytica, P. multocida, Mycoplasma bovis, or Bordetella spp.; cowenteric disease related to infection by E. coli or protozoa (i.e.,coccidia, cryptosporidia, etc.), dairy cow mastitis related to infectionby S. aureus, S. uberis, S. agalactiae, S. dysgalactiae, Klebsiellaspp., Corynebacterium, or Enterococcus spp.; swine respiratory diseaserelated to infection by A. pleuropneumoniae, P. multocida, or Mycoplasmaspp.; swine enteric disease related to infection by E. coli, Lawsoniaintracellularis, Salmonella spp., or Serpulina hyodyisinteriae; cowfootrot related to infection by Fusobacterium spp.; cow metritis relatedto infection by E. coli; cow hairy warts related to infection byFusobacterium necrophorum or Bacteroides nodosus; cow pink-eye relatedto infection by Moraxella bovis, cow premature abortion related toinfection by protozoa (i.e., neosporium); urinary tract infection indogs and cats related to infection by E. coli; skin and soft tissueinfections in dogs and cats related to infection by S. epidermidis, S.intermedius, coagulase neg. Staphylococcus or P. multocida; dental ormouth infections in dogs and goats related to infection by Alcaligenesspp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacteriumspp., Peptostreptococcus spp., Porphfyromonas spp., Campylobacter spp.,Actinomyces spp., Erysipelothrix spp., Rhodococcus spp., Trypanosomaspp., Plasmodium spp., Babesia spp., Toxoplasma spp., Pneumocystis spp.,Leishmania spp., Trichomonas spp. or Prevotella spp. Other bacterialinfections and disorders related to such infections that may be treatedor prevented in accord with the method of the present invention arereferred to in J. P. Sanford at al., “The Sanford Guide To AntimicrobialTherapy,” 26th Edition, (Antimicrobial Therapy, Inc., 1996).

Further bacterial infections and disorders related to such infectionsthat may be treated or prevented in animals include, but are not limitedto, central nervous system infections, external ear infections,infections of the middle ear, such as acute otitis media, infections ofthe cranial sinuses, eye infections, infections of the oral cavity, suchas infections of the teeth, gums and mucosa, upper respiratory tractinfections, lower respiratory tract infections, genitourinaryinfections, gastrointestinal infections, gynecological infections,septicemia, bone and joint infections, skin and skin structureinfections, bacterial endocarditis, burns, antibacterial prophylaxis ofsurgery, antibacterial prophylaxis in immunosuppressed patients, such aspatients receiving cancer chemotherapy, or organ transplant patients andchronic diseases caused by infectious organisms, e.g., arteriosclerosis.

Bacterial protein synthesis requires EF-Tu chaperone proteins. EF-Tu isone of the most abundant proteins in bacteria, as well as one of themost highly conserved, and in a number of species the gene is duplicatedwith identical function. When bound to GTP, EF-Tu can form a complexwith most aminoacylated tRNAs, loading the tRNA onto the ribosome. Inone embodiment, the bacterial infection is associated with the activityof EF-Tu. Without being bound by theory, it is believed that thedisruption of EF-Tu protein activity by the compounds of the inventionwill interfere with protein synthesis and thus bacterial function and/orproliferation. Because EF-Tu is highly conserved across Gram-positiveand Gram-negative bacteria, the compounds of the present invention areuseful for treating infections of both classes of bacteria.

As used herein, the term “EF-Tu-associated state” or “EF-Tu-associateddisorder” include disorders and states (e.g., a disease state) that areassociated with the activity of EF-Tu. A non-limiting example of anEF-Tu associated disorder is a bacterial infection in a subject.

The present invention includes treatment of bacterial infections, aswell as EF-Tu-associated disorders, as described above, but theinvention is not intended to be limited to the manner by which thecompound performs its intended function of treatment of a disease. Thepresent invention includes treatment of diseases described herein in anymanner that allows treatment to occur, e.g., bacterial infection.

In certain embodiments, the invention provides a pharmaceuticalcomposition of any of the compounds of the present invention. In arelated embodiment, the invention provides a pharmaceutical compositionof any of the compounds of the present invention and a pharmaceuticallyacceptable carrier or excipient of any of these compounds. In certainembodiments, the invention includes the compounds as novel chemicalentities.

In one embodiment, the invention includes a packaged bacterial infectiontreatment. The packaged treatment includes a compound of the inventionpackaged with instructions for using an effective amount of the compoundof the invention for an intended use.

The compounds of the present invention are suitable as active agents inpharmaceutical compositions that are efficacious particularly fortreating bacterial infections. The pharmaceutical composition in variousembodiments has a pharmaceutically effective amount of the presentactive agent along with other pharmaceutically acceptable excipients,carriers, fillers, diluents and the like. The phrase, “pharmaceuticallyeffective amount” as used herein indicates an amount necessary toadminister to a host, or to a cell, issue, or organ of a host, toachieve a therapeutic result, especially an anti-bacterial infectioneffect, e.g., inhibition of proliferation of a bacterium, or of anyother bacterial infection.

In other embodiments, the present invention provides a method forinhibiting the activity of an EF-Tu protein. The method includescontacting a cell with any of the compounds of the present invention. Ina related embodiment, the method further provides that the compound ispresent in an amount effective to selectively inhibit the activity of anEF-Tu protein.

In other embodiments, the present invention provides a use of any of thecompounds of the invention for manufacture of a medicament to treat abacterial infection in a subject.

In other embodiments, the invention provides a method of manufacture ofa medicament, including formulating any of the compounds of the presentinvention for treatment of a subject.

Definitions

The term “treat,” “treated,” “treating” or “treatment” includes thediminishment or alleviation of at least one symptom associated or causedby the state, disorder or disease being treated. In certain embodiments,the treatment comprises the induction of a bacterial infection, followedby the activation of the compound of the invention, which would in turndiminish or alleviate at least one symptom associated or caused by thebacterial infection being treated. For example, treatment can bediminishment of one or several symptoms of a disorder or completeeradication of a disorder.

The term “subject” is intended to include organisms, e.g., prokaryotesand eukaryotes, which are capable of suffering from or afflicted with abacterial infection. Examples of subjects include mammals, e.g., humans,dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, andtransgenic non-human animals. In certain embodiments, the subject is ahuman, e.g., a human suffering from, at risk of suffering from, orpotentially capable of suffering from a bacterial infection, and fordiseases or conditions described herein. In another embodiment, thesubject is a cell.

The language “EF-Tu-modulating compound,” “modulator of EF-Tu” or “EF-Tuinhibitor” refers to compounds that modulate, e.g., inhibit, orotherwise alter, the activity of EF-Tu. Examples of EF-Tu-modulatingcompounds include compounds of formula I, formula II, subformulaethereof, as well as compounds of Examples 1-143 (includingpharmaceutically acceptable salts thereof, as well as enantiomers,stereoisomers, rotamers, tautomers, diastereomers, atropisomers orracemates thereof).

Additionally, a method of the invention includes administering to asubject an effective amount of an EF-Tu-modulating compound of theinvention, e.g., EF-Tu-modulating compounds of formula I, formula II,subformulae thereof, as well as compounds of Examples 1-143 (includingpharmaceutically acceptable salts thereof, as well as enantiomers,stereoisomers, rotamers, tautomers, diastereomers, atropisomers orracemates thereof).

The term “alkyl” includes saturated aliphatic groups, includingstraight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups(isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups(cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkylsubstituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.The term “alkyl” also includes alkenyl groups and alkynyl groups.Furthermore, the expression “C_(x)—C_(y)-alkyl”, wherein x is 1-5 and yis 2-10 indicates a particular alkyl group (straight- or branched-chain)of a particular range of carbons. For example, the expressionC₁-C₄-alkyl includes, but is not limited to, methyl, ethyl, propyl,butyl, isopropyl, tert-butyl and isobutyl. Moreover, the termC₃₋₆-cycloalkyl includes, but is not limited to, cyclopropyl,cyclopentyl, and cyclohexyl. As discussed below, these alkyl groups, aswell as cycloalkyl groups, may be further substituted.

The term alkyl further includes alkyl groups which can further includeoxygen, nitrogen, sulfur or phosphorous atoms replacing one or morecarbons of the hydrocarbon backbone. In an embodiment, a straight chainor branched chain alkyl has 10 or fewer carbon atoms in its backbone(e.g., C₁-C₁₀ for straight chain, C₃-C₁₀ for branched chain), and morepreferably 6 or fewer carbons. Likewise, preferred cycloalkyls have from4-7 carbon atoms in their ring structure, and more preferably have 5 or6 carbons in the ring structure.

Moreover, alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl,etc.) include both “unsubstituted alkyl” and “substituted alkyl”, thelatter of which refers to alkyl moieties having substituents replacing ahydrogen on one or more carbons of the hydrocarbon backbone, which allowthe molecule to perform its intended function.

The term “substituted” is intended to describe moieties havingsubstituents replacing a hydrogen on one or more atoms, e.g. C, O or N,of a molecule. Such substituents can include, for example, oxo, alkyl,alkoxy, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, amino (including alkyl amino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, morpholino,phenol, benzyl, phenyl, piperizine, cyclopentane, cyclohexane, pyridine,5H-tetrazole, triazole, piperidine, or an aromatic or heteroaromaticmoiety, and any combination thereof.

Further examples of substituents of the invention, which are notintended to be limiting, include moieties selected from straight orbranched alkyl (preferably C₁-C₅), cycloalkyl (preferably C₃-C₈), alkoxy(preferably C₁-C₆), thioalkyl (preferably C₁-C₆), alkenyl (preferablyC₂-C₆), alkynyl (preferably C₂-C₆), heterocyclic, carbocyclic, aryl(e.g., phenyl), aryloxy (e.g., phenoxy), aralkyl (e.g., benzyl),aryloxyalkyl (e.g., phenyloxyalkyl), arylacetamidoyl, alkylaryl,heteroaralkyl, alkylcarbonyl and arylcarbonyl or other such acyl group,heteroarylcarbonyl, or heteroaryl group, (CR′R″)₀₋₃NR′R″ (e.g., —NH₂),(CR′R″)₀₋₃CN (e.g., —CN), —NO₂, halogen (e.g., —F, —Cl, —Br, or —I),(CR′R″)₀₋₃C(halogen)₃ (e.g., —CF₃), (CR′R″)₀₋₃CH(halogen)₂,(CR′R″)₀₋₃CH₂(halogen), (CR′R″)₀₋₃CONR′R″, (CR′R″)₀₋₃(CNH)NR′R″,(CR′R″)₀₋₃S(O)₁₋₂NR′R″, (CR′R″)₀₋₃CHO, (CR′R″)₀₋₃O(CR′R″)₀₋₃H,(CR′R″)₀₋₃S(O)₀₋₃R′ (e.g., —SO₃H, —OSO₃H), (CR′R″)₀₋₃O(CR′R″)₀₋₃H (e.g.,—CH₂OCH₃ and —OCH₃), (CR′R″)₀₋₃S(CR′R″)₀₋₃H (e.g., —SH and —SCH₃),(CR′R″)₀₋₃OH (e.g., —OH), (CR′R″)₀₋₃COR′, (CR′R″)₀₋₃(substituted orunsubstituted phenyl), (CR′R″)₀₋₃(C₃-C₈ cycloalkyl), (CR′R″)₀₋₃CO₂R′(e.g., —CO₂H), or (CR′R″)₀₋₃OR′ group, or the side chain of anynaturally occurring amino acid; wherein R′ and R″ are each independentlyhydrogen, a C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, or aryl group.Such substituents can include, for example, halogen, hydroxyl,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato,phosphinato, cyano, amino (including alkyl amino, dialkylamino,arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, oxime, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl,cyano, azido, heterocyclyl, or an aromatic or heteroaromatic moiety, andany combination thereof. In certain embodiments, a carbonyl moiety (C═O)may be further derivatized with an oxime moiety, e.g., an aldehydemoiety may be derivatized as its oxime (—C═N—OH) analog. It will beunderstood by those skilled in the art that the moieties substituted onthe hydrocarbon chain can themselves be substituted, if appropriate.Cycloalkyls can be further substituted, e.g., with the substituentsdescribed above. An “aralkyl” moiety is an alkyl substituted with anaryl (e.g., phenylmethyl (i.e., benzyl)).

The term “alkenyl” includes unsaturated aliphatic groups analogous inlength and possible substitution to the alkyls described above, butwhich contain at least one double bond.

For example, the term “alkenyl” includes straight-chain alkenyl groups(e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl,nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl(alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenylgroups, and cycloalkyl or cycloalkenyl substituted alkenyl groups. Theterm alkenyl further includes alkenyl groups that include oxygen,nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone. In certain embodiments, a straight chain orbranched chain alkenyl group has 6 or fewer carbon atoms in its backbone(e.g., C₂-C₆ for straight chain, C₃-C₆ for branched chain). Likewise,cycloalkenyl groups may have from 3-8 carbon atoms in their ringstructure, and more preferably have 5 or 6 carbons in the ringstructure. The term C₂-C₆ includes alkenyl groups containing 2 to 6carbon atoms.

Moreover, the term alkenyl includes both “unsubstituted alkenyls” and“substituted alkenyls”, the latter of which refers to alkenyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, alkylgroups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.

The term “alkynyl” includes unsaturated aliphatic groups analogous inlength and possible substitution to the alkyls described above, butwhich contain at least one triple bond.

For example, the term “alkynyl” includes straight-chain alkynyl groups(e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl,nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkylor cycloalkenyl substituted alkynyl groups. The term alkynyl furtherincludes alkynyl groups that include oxygen, nitrogen, sulfur orphosphorous atoms replacing one or more carbons of the hydrocarbonbackbone. In certain embodiments, a straight chain or branched chainalkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C₂-C₆for straight chain, C₃-C₆ for branched chain). The term C₂-C₆ includesalkynyl groups containing 2 to 6 carbon atoms.

Moreover, the term alkynyl includes both “unsubstituted alkynyls” and“substituted alkynyls”, the latter of which refers to alkynyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, alkylgroups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.

The term “amine” or “amino” should be understood as being broadlyapplied to both a molecule, or a moiety or functional group, asgenerally understood in the art, and may be primary, secondary, ortertiary. The term “amine” or “amino” includes compounds where anitrogen atom is covalently bonded to at least one carbon, hydrogen orheteroatom. The terms include, for example, but are not limited to,“alkylamino,” “arylamino,” “diarylamino,” “alkylarylamino,”“alkylaminoaryl,” “arylaminoalkyl,” “alkaminoalkyl,” “amide,” “amido,”and “aminocarbonyl.” The term “alkyl amino” comprises groups andcompounds wherein the nitrogen is bound to at least one additional alkylgroup. The term “dialkyl amino” includes groups wherein the nitrogenatom is bound to at least two additional alkyl groups. The term“arylamino” and “diarylamino” include groups wherein the nitrogen isbound to at least one or two aryl groups, respectively. The term“alkylarylamino,” “alkylaminoaryl” or “arylaminoalkyl” refers to anamino group which is bound to at least one alkyl group and at least onearyl group. The term “alkaminoalkyl” refers to an alkyl, alkenyl, oralkynyl group bound to a nitrogen atom which is also bound to an alkylgroup.

The term “amide,” “amido” or “aminocarbonyl” includes compounds ormoieties which contain a nitrogen atom which is bound to the carbon of acarbonyl or a thiocarbonyl group. The term includes “alkaminocarbonyl”or “alkylaminocarbonyl” groups which include alkyl, alkenyl, aryl oralkynyl groups bound to an amino group bound to a carbonyl group. Itincludes arylaminocarbonyl and arylcarbonylamino groups which includearyl or heteroaryl moieties bound to an amino group which is bound tothe carbon of a carbonyl or thiocarbonyl group. The terms“alkylaminocarbonyl,” “alkenylaminocarbonyl,” “alkynylaminocarbonyl,”“arylaminocarbonyl,” “alkylcarbonylamino,” “alkenylcarbonylamino,”“alkynylcarbonylamino,” and “arylcarbonylamino” are included in term“amide.” Amides also include urea groups (aminocarbonylamino) andcarbamates (oxycarbonylamino).

The term “aryl” includes groups, including 5- and 6-membered single-ringaromatic groups that may include from zero to four heteroatoms, forexample, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole,imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine,pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, theterm “aryl” includes multicyclic aryl groups, e.g., tricyclic, bicyclic,e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole,benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline,isoquinoline, anthryl, phenanthryl, napthridine, indole, benzofuran,purine, benzofuran, deazapurine, or indolizine. Those aryl groups havingheteroatoms in the ring structure may also be referred to as “arylheterocycles”, “heterocycles,” “heteroaryls” or “heteroaromatics.” Thearomatic ring can be substituted at one or more ring positions with suchsubstituents as described above, as for example, alkyl, halogen,hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl,aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino(including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Arylgroups can also be fused or bridged with alicyclic or heterocyclic ringswhich are not aromatic so as to form a polycycle (e.g., tetralin).

The term heteroaryl, as used herein, represents a stable monocyclic orbicyclic ring of up to 7 atoms in each ring, wherein at least one ringis aromatic and contains from 1 to 4 heteroatoms selected from the groupconsisting of O, N and S. Heteroaryl groups within the scope of thisdefinition include but are not limited to: acridinyl, carbazolyl,cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl,thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl,oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetrahydroquinoline. As with the definition ofheterocycle below, “heteroaryl” is also understood to include theN-oxide derivative of any nitrogen-containing heteroaryl. In cases wherethe heteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, it is understood that attachment is via thearomatic ring or via the heteroatom containing ring, respectively.

The term “heterocycle” or “heterocyclyl” as used herein is intended tomean a 5- to 10-membered aromatic or nonaromatic heterocycle containingfrom 1 to 4 heteroatoms selected from the group consisting of O, N andS, and includes bicyclic groups. “Heterocyclyl” therefore includes theabove mentioned heteroaryls, as well as dihydro and tetrahydro analogsthereof. Further examples of “heterocyclyl” include, but are not limitedto the following: benzoimidazolyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl,indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. Attachment of a heterocyclyl substituent can occur viaa carbon atom or via a heteroatom.

The term “acyl” includes compounds and moieties which contain the acylradical (CH₃CO—) or a carbonyl group. The term “substituted acyl”includes acyl groups where one or more of the hydrogen atoms arereplaced by for example, alkyl groups, alkynyl groups, halogens,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano,amino (including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

The term “acylamino” includes moieties wherein an acyl moiety is bondedto an amino group. For example, the term includes alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido groups.

The term “alkoxy” includes substituted and unsubstituted alkyl, alkenyl,and alkynyl groups covalently linked to an oxygen atom. Examples ofalkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy,and pentoxy groups and may include cyclic groups such as cyclopentoxy.Examples of substituted alkoxy groups include halogenated alkoxy groups.The alkoxy groups can be substituted with groups such as alkenyl,alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkyl amino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moieties. Examples of halogen substituted alkoxygroups include, but are not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc.

The term “carbonyl” or “carboxy” includes compounds and moieties whichcontain a carbon connected with a double bond to an oxygen atom, andtautomeric forms thereof. Examples of moieties that contain a carbonylinclude aldehydes, ketones, carboxylic acids, amides, esters,anhydrides, etc. The term “carboxy moiety” or “carbonyl moiety” refersto groups such as “alkylcarbonyl” groups wherein an alkyl group iscovalently bound to a carbonyl group, “alkenylcarbonyl” groups whereinan alkenyl group is covalently bound to a carbonyl group,“alkynylcarbonyl” groups wherein an alkynyl group is covalently bound toa carbonyl group, “arylcarbonyl” groups wherein an aryl group iscovalently attached to the carbonyl group. Furthermore, the term alsorefers to groups wherein one or more heteroatoms are covalently bondedto the carbonyl moiety. For example, the term includes moieties such as,for example, aminocarbonyl moieties, (wherein a nitrogen atom is boundto the carbon of the carbonyl group, e.g., an amide), aminocarbonyloxymoieties, wherein an oxygen and a nitrogen atom are both bond to thecarbon of the carbonyl group (e.g., also referred to as a “carbamate”).Furthermore, aminocarbonylamino groups (e.g., ureas) are also include aswell as other combinations of carbonyl groups bound to heteroatoms(e.g., nitrogen, oxygen, sulfur, etc. as well as carbon atoms).Furthermore, the heteroatom can be further substituted with one or morealkyl, alkenyl, alkynyl, aryl, aralkyl, acyl, etc. moieties.

The term “thiocarbonyl” or “thiocarboxy” includes compounds and moietieswhich contain a carbon connected with a double bond to a sulfur atom.The term “thiocarbonyl moiety” includes moieties that are analogous tocarbonyl moieties. For example, “thiocarbonyl” moieties includeaminothiocarbonyl, wherein an amino group is bound to the carbon atom ofthe thiocarbonyl group, furthermore other thiocarbonyl moieties include,oxythiocarbonyls (oxygen bound to the carbon atom),aminothiocarbonylamino groups, etc.

The term “ether” includes compounds or moieties that contain an oxygenbonded to two different carbon atoms or heteroatoms. For example, theterm includes “alkoxyalkyl” which refers to an alkyl, alkenyl, oralkynyl group covalently bonded to an oxygen atom that is covalentlybonded to another alkyl group.

The term “ester” includes compounds and moieties that contain a carbonor a heteroatom bound to an oxygen atom that is bonded to the carbon ofa carbonyl group. The term “ester” includes alkoxycarboxy groups such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynyl groups are asdefined above.

The term “thioether” includes compounds and moieties which contain asulfur atom bonded to two different carbon or hetero atoms. Examples ofthioethers include, but are not limited to alkthioalkyls,alkthioalkenyls, and alkthioalkynyls. The term “alkthioalkyls” includecompounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfuratom that is bonded to an alkyl group. Similarly, the term“alkthioalkenyls” and alkthioalkynyls” refer to compounds or moietieswherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atomwhich is covalently bonded to an alkynyl group.

The term “hydroxy” or “hydroxyl” includes groups with an —H or —O⁻.

The term “halogen” includes fluorine, bromine, chlorine, iodine, etc.The term “perhalogenated” generally refers to a moiety wherein allhydrogens are replaced by halogen atoms.

The terms “polycyclyl” or “polycyclic radical” include moieties with twoor more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, arylsand/or heterocyclyls) in which two or more carbons are common to twoadjoining rings, e.g., the rings are “fused rings”. Rings that arejoined through non-adjacent atoms are termed “bridged” rings. Each ofthe rings of the polycycle can be substituted with such substituents asdescribed above, as for example, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl,aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl,alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (includingalkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl,alkylaryl, or an aromatic or heteroaromatic moiety.

The term “heteroatom” includes atoms of any element other than carbon orhydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur andphosphorus.

Additionally, the phrase “any combination thereof” implies that anynumber of the listed functional groups and molecules may be combined tocreate a larger molecular architecture. For example, the terms “phenyl,”“carbonyl” (or “═O”), “—O—,” “—OH,” and C₁₋₆ (i.e., —CH₃ and—CH₂CH₂CH₂—) can be combined to form a 3-methoxy-4-propoxybenzoic acidsubstituent. It is to be understood that when combining functionalgroups and molecules to create a larger molecular architecture,hydrogens can be removed or added, as required to satisfy the valence ofeach atom.

It is to be understood that all of the compounds of the inventiondescribed above will further include bonds between adjacent atoms and/orhydrogens as required to satisfy the valence of each atom. That is,bonds and/or hydrogen atoms are added to provide the following number oftotal bonds to each of the following types of atoms: carbon: four bonds;nitrogen: three bonds; oxygen: two bonds; and sulfur: two-six bonds.

It will be noted that the structures of some of the compounds of thisinvention include asymmetric carbon atoms. It is to be understoodaccordingly that the isomers arising from such asymmetry (e.g., allenantiomers, stereoisomers, rotamers, tautomers, diastereomers, orracemates) are included within the scope of this invention. Such isomerscan be obtained in substantially pure form by classical separationtechniques and by stereochemically controlled synthesis. Furthermore,the structures and other compounds and moieties discussed in thisapplication also include all tautomers thereof. Compounds describedherein may be obtained through art recognized synthesis strategies.

It will also be noted that the substituents of some of the compounds ofthis invention include isomeric cyclic structures. It is to beunderstood accordingly that constitutional isomers of particularsubstituents are included within the scope of this invention, unlessindicated otherwise. For example, the term “tetrazole” includestetrazole, 2H-tetrazole, 3H-tetrazole, 4H-tetrazole and 5H-tetrazole.

Use in Bacterial Infection

The compounds of the present invention have valuable pharmacologicalproperties and are useful in the treatment of diseases. In certainembodiments, compounds of the invention are useful in the treatment ofbacterial infections.

The term “use” includes any one or more of the following embodiments ofthe invention, respectively: the use in the treatment of bacterialinfections; the use for the manufacture of pharmaceutical compositionsfor use in the treatment of these diseases, e.g., in the manufacture ofa medicament; methods of use of compounds of the invention in thetreatment of these diseases; pharmaceutical preparations havingcompounds of the invention for the treatment of these diseases; andcompounds of the invention for use in the treatment of these diseases;as appropriate and expedient, if not stated otherwise. In particular,diseases to be treated and are thus preferred for use of a compound ofthe present invention are selected from bacterial infections, as well asthose diseases that depend on the activity of EF-Tu. The term “use”further includes embodiments of compositions herein which bind to anEF-Tu protein sufficiently to serve as tracers or labels, so that whencoupled to a fluor or tag, or made radioactive, can be used as aresearch reagent or as a diagnostic or an imaging agent.

In certain embodiments, a compound of the present invention is used fortreating EF-Tu-associated diseases, and use of the compound of thepresent invention as an inhibitor of any one or more EF-Tu proteins. Itis envisioned that a use can be a treatment of inhibiting one or moreisoforms of EF-Tu.

Assays

The inhibition of antibacterial activity by the compounds of theinvention may be measured using a number of assays available in the art.An example of such an assay is the standard minimum inhibitoryconcentration (MIC) test conducted according to CSLI guidelines.

Pharmaceutical Compositions

The language “effective amount” of the compound is that amount necessaryor sufficient to treat or prevent a bacterial infection, e.g. preventthe various morphological and somatic symptoms of a bacterial infection,and/or a disease or condition described herein. In an example, aneffective amount of the compound of the invention is the amountsufficient to treat a bacterial infection in a subject. The effectiveamount can vary depending on such factors as the size and weight of thesubject, the type of illness, or the particular compound of theinvention. For example, the choice of the compound of the invention canaffect what constitutes an “effective amount.” One of ordinary skill inthe art would be able to study the factors contained herein and make thedetermination regarding the effective amount of the compounds of theinvention without undue experimentation.

The regimen of administration can affect what constitutes an effectiveamount. The compound of the invention can be administered to the subjecteither prior to or after the onset of a bacterial infection. Further,several divided dosages, as well as staggered dosages, can beadministered daily or sequentially, or the dose can be continuouslyinfused, or can be a bolus injection. Further, the dosages of thecompound(s) of the invention can be proportionally increased ordecreased as indicated by the exigencies of the therapeutic orprophylactic situation.

Compounds of the invention may be used in the treatment of states,disorders or diseases as described herein, or for the manufacture ofpharmaceutical compositions for use in the treatment of these diseases.Methods of use of compounds of the present invention in the treatment ofthese diseases, or pharmaceutical preparations having compounds of thepresent invention for the treatment of these diseases.

The language “pharmaceutical composition” includes preparations suitablefor administration to mammals, e.g., humans. When the compounds of thepresent invention are administered as pharmaceuticals to mammals, e.g.,humans, they can be given per se or as a pharmaceutical compositioncontaining, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) ofactive ingredient in combination with a pharmaceutically acceptablecarrier.

The phrase “pharmaceutically acceptable carrier” is art recognized andincludes a pharmaceutically acceptable material, composition or vehicle,suitable for administering compounds of the present invention tomammals. The carriers include liquid or solid filler, diluent,excipient, solvent or encapsulating material, involved in carrying ortransporting the subject agent from one organ, or portion of the body,to another organ, or portion of the body. Each carrier must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not injurious to the patient. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude: sugars, such as lactose, glucose and sucrose; starches, such ascorn starch and potato starch; cellulose, and its derivatives, such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients, such as cocoabutter and suppository waxes; oils, such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols, such as glycerin, sorbitol, mannitoland polyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar; buffering agents, such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol; phosphate buffer solutions; and other non-toxiccompatible substances employed in pharmaceutical formulations.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like;oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, α-tocopherol, and the like; and metal chelating agents, such ascitric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaricacid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical, buccal, sublingual, rectal, vaginal and/or parenteraladministration. The formulations may conveniently be presented in unitdosage form and may be prepared by any methods well known in the art ofpharmacy. The amount of active ingredient that can be combined with acarrier material to produce a single dosage form will generally be thatamount of the compound that produces a therapeutic effect. Generally,out of one hundred percent, this amount will range from about 1 percentto about ninety-nine percent of active ingredient, preferably from about5 percent to about 70 percent, most preferably from about 10 percent toabout 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theactive ingredient is mixed with one or more pharmaceutically acceptablecarriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: fillers or extenders, such as starches, lactose, sucrose,glucose, mannitol, and/or silicic acid; binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; humectants, such as glycerol; disintegratingagents, such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; solutionretarding agents, such as paraffin; absorption accelerators, such asquaternary ammonium compounds; wetting agents, such as, for example,cetyl alcohol and glycerol monostearate; absorbents, such as kaolin andbentonite clay; lubricants, such a talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof; and coloring agents. In the case of capsules, tabletsand pills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions that can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use. These compositions may also optionally containopacifying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions that can be used include polymeric substances andwaxes. The active ingredient can also be in micro-encapsulated form, ifappropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluent commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants that may berequired.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the activecompound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacteriostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents that delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissue.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given by formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc., administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral and/or IV administration is preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracistemally and topically, as by powders, ointments ordrops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular compound employed, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound that is the lowest dose effective to producea therapeutic effect. Such an effective dose will generally depend uponthe factors described above. Generally, intravenous and subcutaneousdoses of the compounds of this invention for a patient, when used forthe indicated analgesic effects, will range from about 0.0001 to about100 mg per kilogram of body weight per day, more preferably from about0.01 to about 50 mg per kg per day, and still more preferably from about1.0 to about 100 mg per kg per day. An effective amount is that amounttreats a bacterial infection.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical composition.

Synthetic Procedure

Compounds of the present invention are prepared from commonly availablecompounds using procedures known to those skilled in the art, includingany one or more of the following conditions without limitation:

Within the scope of this text, only a readily removable group that isnot a constituent of the particular desired end product of the compoundsof the present invention is designated a “protecting group,” unless thecontext indicates otherwise. The protection of functional groups by suchprotecting groups, the protecting groups themselves, and their cleavagereactions are described for example in standard reference works, such ase.g., Science of Synthesis: Houben-Weyl Methods of MolecularTransformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627 pp.(URL: http://www.science-of-synthesis.com (Electronic Version, 48Volumes)); J. F. W. McOmie, “Protective Groups in Organic Chemistry”,Plenum Press, London and New York 1973, in T. W. Greene and P. G. M.Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley,New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross and J.Meienhofer), Academic Press, London and New York 1981, in “Methoden derorganischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4thedition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974, in H.-D.Jakubke and H. Jeschkeit, “Aminosäuren, Peptide, Proteine” (Amino acids,Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel1982, and in Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharideund Derivate” (Chemistry of Carbohydrates: Monosaccharides andDerivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic ofprotecting groups is that they can be removed readily (i.e., without theoccurrence of undesired secondary reactions) for example by solvolysis,reduction, photolysis or alternatively under physiological conditions(e.g., by enzymatic cleavage).

Salts of compounds of the present invention having at least onesalt-forming group may be prepared in a manner known per se. Forexample, salts of compounds of the present invention having acid groupsmay be formed, for example, by treating the compounds with metalcompounds, such as alkali metal salts of suitable organic carboxylicacids, e.g., the sodium salt of 2-ethylhexanoic acid, with organicalkali metal or alkaline earth metal compounds, such as thecorresponding hydroxides, carbonates or hydrogen carbonates, such assodium or potassium hydroxide, carbonate or hydrogen carbonate, withcorresponding calcium compounds or with ammonia or a suitable organicamine, stoichiometric amounts or only a small excess of the salt-formingagent preferably being used. Acid addition salts of compounds of thepresent invention are obtained in customary manner, e.g., by treatingthe compounds with an acid or a suitable anion exchange reagent.Internal salts of compounds of the present invention containing acid andbasic salt-forming groups, e.g., a free carboxy group and a free aminogroup, may be formed, e.g., by the neutralisation of salts, such as acidaddition salts, to the isoelectric point, e.g., with weak bases, or bytreatment with ion exchangers.

Salts can be converted in customary manner into the free compounds;metal and ammonium salts can be converted, for example, by treatmentwith suitable acids, and acid addition salts, for example, by treatmentwith a suitable basic agent.

Mixtures of isomers obtainable according to the invention can beseparated in a manner known per se into the individual isomers;diastereoisomers can be separated, for example, by partitioning betweenpolyphasic solvent mixtures, recrystallisation and/or chromatographicseparation, for example over silica gel or by, e.g., medium pressureliquid chromatography over a reversed phase column, and racemates can beseparated, for example, by the formation of salts with optically puresalt-forming reagents and separation of the mixture of diastereoisomersso obtainable, for example by means of fractional crystallisation, or bychromatography over optically active column materials.

Intermediates and final products can be worked up and/or purifiedaccording to standard methods, e.g., using chromatographic methods,distribution methods, (re-) crystallization, and the like.

General Process Conditions

The following applies in general to all processes mentioned throughoutthis disclosure.

The process steps to synthesize the compounds of the invention can becarried out under reaction conditions that are known per se, includingthose mentioned specifically, in the absence or, customarily, in thepresence of solvents or diluents, including, for example, solvents ordiluents that are inert towards the reagents used and dissolve them, inthe absence or presence of catalysts, condensation or neutralizingagents, for example ion exchangers, such as cation exchangers, e.g., inthe H⁺ form, depending on the nature of the reaction and/or of thereactants at reduced, normal or elevated temperature, for example in atemperature range of from about −100° C. to about 190° C., including,for example, from approximately −80° C. to approximately 150° C., forexample at from −80 to −60° C., at room temperature, at from −20 to 40°C. or at reflux temperature, under atmospheric pressure or in a closedvessel, where appropriate under pressure, and/or in an inert atmosphere,for example under an argon or nitrogen atmosphere.

At all stages of the reactions, mixtures of isomers that are formed canbe separated into the individual isomers, for example diastereoisomersor enantiomers, or into any desired mixtures of isomers, for exampleracemates or mixtures of diastereoisomers, for example analogously tothe methods described in Science of Synthesis: Houben-Weyl Methods ofMolecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005.

The solvents from which those solvents that are suitable for anyparticular reaction may be selected include those mentioned specificallyor, for example, water, esters, such as lower alkyl-lower alkanoates,for example ethyl acetate, ethers, such as aliphatic ethers, for examplediethyl ether, or cyclic ethers, for example tetrahydrofurane ordioxane, liquid aromatic hydrocarbons, such as benzene or toluene,alcohols, such as methanol, ethanol or 1- or 2-propanol, nitriles, suchas acetonitrile, halogenated hydrocarbons, such as methylene chloride orchloroform, acid amides, such as dimethylformamide or dimethylacetamide, bases, such as heterocyclic nitrogen bases, for examplepyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, suchas lower alkanoic acid anhydrides, for example acetic anhydride, cyclic,linear or branched hydrocarbons, such as cyclohexane, hexane orisopentane, or mixtures of those solvents, for example aqueoussolutions, unless otherwise indicated in the description of theprocesses. Such solvent mixtures may also be used in working up, forexample by chromatography or partitioning.

The compounds, including their salts, may also be obtained in the formof hydrates, or their crystals may, for example, include the solventused for crystallization. Different crystalline forms may be present.

The invention relates also to those forms of the process in which acompound obtainable as an intermediate at any stage of the process isused as starting material and the remaining process steps are carriedout, or in which a starting material is formed under the reactionconditions or is used in the form of a derivative, for example in aprotected form or in the form of a salt, or a compound obtainable by theprocess according to the invention is produced under the processconditions and processed further in situ.

Prodrugs

This invention also encompasses pharmaceutical compositions containing,and methods of treating bacterial infections through administering,pharmaceutically acceptable prodrugs of compounds of the compounds ofthe invention. For example, compounds of the invention having freeamino, amido, hydroxy or carboxylic groups can be converted intoprodrugs. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues is covalently joined through an amide or ester bond to a freeamino, hydroxy or carboxylic acid group of compounds of the invention.The amino acid residues include but are not limited to the 20 naturallyoccurring amino acids commonly designated by three letter symbols andalso includes 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.Additional types of prodrugs are also encompassed. For instance, freecarboxyl groups can be derivatized as amides or alkyl esters. Freehydroxy groups may be derivatized using groups including but not limitedto hemisuccinates, phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug DeliveryReviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and amino groupsare also included, as are carbonate prodrugs, sulfonate esters andsulfate esters of hydroxy groups. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group may bean alkyl ester, optionally substituted with groups including but notlimited to ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med. Chem. 1996,39, 10. Free amines can also be derivatized as amides, sulfonamides orphosphonamides. All of these prodrug moieties may incorporate groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities.

Any reference to a compound of the present invention is therefore to beunderstood as referring also to the corresponding pro-drugs of thecompound of the present invention, as appropriate and expedient.

Combinations

A compound of the present invention may also be used in combination withother agents, e.g., an additional antibacterial compound that is or isnot a compound of the invention, for treatment of a bacterial infectionin a subject.

By the term “combination” is meant either a fixed combination in onedosage unit form, or a kit of parts for the combined administrationwhere a compound of the present invention and a combination partner maybe administered independently at the same time or separately within timeintervals that especially allow that the combination partners show acooperative, e.g., synergistic, effect, or any combination thereof.

A compound of the present invention may be used in combination withanother antibacterial agent. The term “antibacterial agent” refers toany substance that is either bactericidal or bacteriostatic, i.e.,capable of killing or inhibiting the growth of bacterial cells.Antibacterial agents include antibiotics, biocides, antimicrobials, andbacteriostatic agents. The known types of antibiotics include, e.g.,cell wall synthesis inhibitors, cell membrane inhibitors, proteinsynthesis inhibitors and inhibitors that bind to or affect the synthesisof DNA or RNA. Numerous antibiotic agents suitable for use in thetreatment of bacteria-related diseases and disorders, are known anddisclosed, e.g. in The Physician's Desk Reference (PDR), MedicalEconomics Company (Montvale, N.J.), (53.sup.rd Ed.), 1999; Mayo MedicalCenter Formulary, Unabridged Version, Mayo Clinic (Rochester, Minn.),January 1998; Merck Index: An Encyclopedia of Chemicals, Drugs andBiologicals, (11.sup.th Ed.), Merck & Co., Inc. (Rahway, N.J.), 1989;University of Wisconsin Antimicrobial Use Guide,http://www.medsch.wisc.edu/clinsci/5amcg/amcg.html; Introduction on theUse of the Antibiotics Guideline, of Specific Antibiotic Classes, ThomasJefferson University,http://jeffiine.tju.edu/CWIS/OAC/antibiotics_guide/intro.html; andreferences cited therein.

Examples of antibiotics for use in combination with the compounds of theinvention include, but are not limited to, quinolone, macrolide,glycopeptide, oxazolidinone, β-lactams (including amoxicillin,ampicillin, bacampicillin, carbenicillin, cloxacillin, dicloxacillin,flucloxacillin, methicillin, mezlocillin, nafcillin, oxacillin,penicillin G, penicillin V, piperacillin, pivampicillin, pivmecillinam,ticarcillin, sulbactam, tazobactam, clavulanate), daptomycin,cephalosporins (cefaclor, cefadroxil, cefamandole, cefazolin, cefdinir,cefditoren, cefepime, cefixime, cefonicid, cefoperazone, cefotaxime,cefotetan, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten,ceftizoxime, ceftriaxone, cefuroxime, cephalexin, cephalothin,cephapirin, cephradine), aminoglycosides (including gentamycin,streptomycin, amikacin, kanamycin, viomycin, capreomycin), ethionamide,prothionamide, cycloserine, dapsone, clofazimine, tetracyclines(tetracycline, doxycycline, chlortetracycline, oxytetracycline,minocycline demeclocycline), oxazolidinones (linezolid, eperezolid),metronidazole, rifabutin, isoniazonid, ethambutol, and combinationsthereof.

Examples of anti-viral agents for use in combination with the compoundsof the invention include, but are not limited to, zidovudine,lamivudine, didanosine, zalcitabine, stavudine, abacavir, nevirapine,delavirdine, emtricitabine, efavirenz, saquinavir, ritonavir, indinavir,nelfinavir, amprenavir, tenofovir, adefovir, atazanavir, fosamprenavir,hydroxyurea, AL-721, ampligen, butylated hydroxytoluene;polymannoacetate, castanospermine; contracan; creme pharmatex, CS-87,penciclovir, famciclovir, acyclovir, cytofovir, ganciclovir, dextransulfate, D-penicillamine trisodium phosphonoformate, fusidic acid,HPA-23, eflornithine, nonoxynol, pentamidine isethionate, peptide T,phenyloin, isoniazid, ribavirin, rifabutin, ansamycin, trimetrexate,SK-818, suramin, UA001, enfuvirtide, gp41-derived peptides, antibodiesto CD4, soluble CD4, CD4-containing molecules, CD4-IgG2, andcombinations thereof.

Further examples of agents the compounds of the present invention can beused in combination with include, but are not limited to, free radicalscavengers, ascorbic acid, Vitamin C, anti-cancer agents,chemotherapeutic agents, non-steroidal anti-inflammatory drugs,steroidal anti-inflammatory drugs, anti-fungal agents, detoxifyingagents, analgesics, bronchodilators, drugs for the treatment of vascularischemia anti-body monoclonal agent, minoxidil for topical applicationfor hair growth, diuretics, immunosuppressants, lymphokynes,α-and-β-interferon and combinations thereof.

The compound of the invention and any additional agent may be formulatedin separate dosage forms. Alternatively, to decrease the number ofdosage forms administered to a patient, the compound of the inventionand any additional agent may be formulated together in any combination.For example, the compound of the invention inhibitor may be formulatedin one dosage form and the additional agent may be formulated togetherin another dosage form. Any separate dosage forms may be administered atthe same time or different times.

Alternatively, a composition of this invention comprises an additionalagent as described herein. Each component may be present in individualcompositions, combination compositions, or in a single composition.

EXEMPLIFICATION OF THE INVENTION

The invention is further illustrated by the following examples, whichshould not be construed as further limiting. The practice of the presentinvention will employ, unless otherwise indicated, conventionaltechniques of cell biology, cell culture, molecular biology, transgenicbiology, microbiology and immunology, which are within the skill of theart.

General Synthesis Methods

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

EXAMPLES

Definitions AcOH acetic acid aq aqueous boc tert-butoxycarbonyl CCelsius cat. catalyst CDI cabonyldiimidazole conc. concentrated C₂CO₃cesium carbonate deg. degrees DIPEA diisopropylethylamine DIPCN,N′-diisopropylcarbodiimide DMF N,N-dimethylformamide DCCN,N-dicyclohexylcarbodiimide DCE dichloroethane DCM dichloromethane DMAP4-dimethylaminopyridine DMSO dimethylsulfoxide EtOAc ethyl acetate EtOHethanol eq equivalents HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate Hep heptane HCl hydrochloric acid K₂CO₃ potassiumcarbonate LiBH₄ lithium borohydride LC liquid chromatography LCMS liquidchromatography mass spectrum MeOH methanol MgSO₄ magnesium sulfate MHzmegahertz NaBH₄ sodium borohydride Pd/C palladium on carbon PEG(750)O-(2-aminoethyl)-O′-methyl polyethylene glycol 750; NH₂(CH₂CH₂O)_(n)CH₃;CAS#[80506-64-5]; Fluka 07964; AVERAGE MW = 750 PS polystyrene Pypyridine RP reverse phase RT room temperature R_(t) retention time ssolid sat. saturated TBTUO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate TLCthin-layer chromatography TEA triethylamine TFA trifluoroacetic acid THFtetrahydrofuran h hours min minutes m/z mass to charge MS mass spectrumHRMS high resolution mass spectrum NMR nuclear magnetic resonanceAnalytical Methods

-   NMR: proton spectra are recorded on a Bruker 400 MHz ultrashield    spectrometer. Chemical shifts are reported relative to methanol (δ    3.31), dimethyl sulfoxide (δ 2.50), or chloroform (δ 7.26).

LC/MS:

-   Method 1: compounds are analyzed on an Inertsil ODS-3 column (C18,    50×4.6 mm, 3 μm) with a 2 min gradient elution (20-80%    acetonitrile/H₂O/5 mM ammonium formate) and a flow rate of 4 ml/min.-   Method 5: GENERAL LC-MS method with acid mobile phase (0.1% formic    acid) and fast gradient. Electrospray mass spectra (+) and (−),    DAD-UV chromatogram 200-400 nm, scan range 120-1500 Da. Gradient:    20-80% MeCN/H₂O in 2 min (2 mL/min), 2 μL injection. Column:    Inertsil ODS3 C-18, 3 cm×33 mm×3.0 μm, 40 deg C.-   Method 6: GENERAL LC-MS method with neutral mobile phase (5 mM NH₄    ⁺HCOO⁻) and fast (20-80%) gradient. Electrospray mass spectra (+)    and (−), DAD-UV chromatogram 200-400 nm, scan range 120-1500 Da.    Gradient: 20-80% MeCN/H₂O in 2 min (2 mL/min), 2 μL injection.    Column: Inertsil ODS3 C-18, 3 cm×33 mm×3.0 μm, 40 deg C.-   Method 7: LC-MS method for NON-POLAR (greasy) compounds with acid    mobile phase (0.1% formic acid) and fast (40-90%) gradient.    Electrospray mass spectra (+) and (−), DAD-UV chromatogram 200-400    nm, scan range 120-1500 Da. Gradient: 40-90% MeCN/H₂O in 2 min (2    mL/min), 2 μL injection. Column: Inertsil C8-3, 3 cm×33 mm×3.0 μm,    40 deg C.-   Method 8: LC-MS method for NON-POLAR (greasy) compounds with neutral    mobile phase (5 mM NH₄ ⁺HCOO⁻) and fast (40-90%) gradient.    Electrospray mass spectra (+) and (−), DAD-UV chromatogram 200-400    nm, scan range 120-1500 Da. Gradient: 40-90% MeCN/H₂O in 2 min (2    mL/min), 2 μL injection. Column: Inertsil C8-3, 3.0 cm×33 mm×3.0 μm,    40 deg C.-   Method 9: LC-MS method with broad range (5-95%) gradient with acid    mobile phase (0.1% Formic Acid). Electrospray mass spectra (+) and    (−), DAD-UV chromatogram 200-400 nm, scan range 120-1500 Da.    Gradient: 5-95% MeCN/H₂O in 2 min (2 mL/min), 2 μL injection.    Column: Inertsil C8-3, 3.0 cm×33 mm×3.0 μm, 40 deg C.-   Method 10: LC-MS method with broad range (5-95%) gradient with    neutral mobile phase (5 mM NH₄ ⁺HCOO⁻). Electrospray mass spectra    (+) and (−), DAD-UV chromatogram 200-400 nm, scan range 120-1500 Da.    Gradient: 5-95% MeCN/H₂O in 2 min (2 mL/min), 2 μL injection.    Column: Inertsil C8-3, 3 cm×433 mm×3.0 μm, 40 deg C.-   Method 11: LC-MS method for POLAR compounds with acid mobile phase    (0.1% formic acid) and slow (0-100%) gradient. Electrospray mass    spectra (+) and (−), DAD-UV chromatogram 200-400 nm, scan range    120-1500 Da. Gradient: 0-100% MeCN/H₂O in 2 min (2 mL/min), 2 μL    injection. Column: Inertsil ODS3 (C-18, 3 cm×33 mm×3.0 μm, 40 degree    C.)-   Method 12: LC-MS method for POLAR compounds with neutral mobile    phase (5 mM NH₄ ⁺HCOO⁻) and slow (0-100%) gradient. Electrospray    mass spectra (+) and (−), DAD-UV chromatogram 200-400 nm, scan range    120-1500 Da. Gradient: 0-100% MeCN/H₂O in 2 min (2 mL/min), 2 μL    injection. Column: Inertsil ODS-3 (C-18, 3 cm×33 mm×3.0 μm, 40 deg    C.-   Method 13: Compounds are analyzed on an Inertsil ODS-3 column (C8,    30 mm×3.0 mm, 3.0 μm) with a 2 min gradient elution (5-90%    acetonitrile/H₂O/5 mM ammonium formate) and a flow rate of 2 ml/min.-   Method 14: Compounds are analyzed on an Inertsil ODS-3 column (C8,    30 mm×3.0 mm, 3.0 μm) with a 2 min gradient elution (5-90%    acetonitrile/H₂O/0.1% formic acid) and a flow rate of 2 ml/min.-   HPLC purification utilizes a C8 or C18 column (30×100 mm, 5 μm,    brand: Sunfire or XTerra) and is performed with an appropriate    gradient according to two methods (unless otherwise noted). Method 1    consists of 0.1% TFA in 5%-95% ACN in H₂O. Method 2 consists of 10    mM NH₄OH in 5%-95% ACN in H₂O.-   LC analysis utilizes a liquid chromatography-UV detection (LC-UV)    using a Agilent 1100 liquid chromatograph. LC conditions were as    follows:-   Column: Atlantis C18 (Waters, Inc.), 15 cm×4.6 mm×5 μm; column    temperature: ambient; flow rate: 1.4 mL/min; injection volume: 3.0    μL; gradient: A=0.1% trifluoroacetic acid (TFA) in water, B=0.05%    trifluoroacetic Acid (TFA) in acetonitrile, 0-95% B in 19.0 min, 1.8    min hold.

The compound of general formula (I) may be prepared via syntheticmethods known to those skilled in the art, or alternatively isolatedfrom a fermentation broth. The compound of general structural formula(II) may be prepared by process A by the acid or base mediatedalkylation of compound (i) in the presence of an electrophile.

The compound of general formula (iii) may be prepared in process B from(i) via an acid or base catalyzed reaction which removes thedehydroalanine sidechain or part thereof. This process may or may notconcomitantly open the epoxide to provide iii. The compounds of generalformulae iv may be prepared from compound iii via acid or base catalyzedalkylation, oxidation, reduction, amidation, or protection according toprocess C. Compounds of general formulae v and vi may be prepared viaacid or base mediated ring closure according to process D. Compoundsvii, viii may be prepared from compounds v, vi in process E via an acidor base mediated alkylation, acylation, retroaldol trapping, amination,amidation, oxidation, reduction, protection, or deprotection. A suitableprotecting group can be selected by those skilled in the art. Protectinggroups are selected so that they are suitable for the depictedtransformations and can be removed following the synthesis with littleor no loss of yield. The introduction and selective removal ofprotecting groups are taught in Greene and Wuts, “Protective Groups inOrganic Synthesis”, John Wiley & Sons (1991). Alternatively, any ofthese steps (A-E) may be performed in a different order, or with somesteps removed or slightly altered.

Example 1 Preparation of Methylester (2)

To a solution of acid (1, 45 mg, 0.747 mmol) in DMF (1 mL) is addedCs₂CO₃ (10 mg) and iodomethane (30 uL, 1.5 M solution in DMF). Thesolution is stirred at RT for 1 h, MeOH is added (3 mL) and the reactionis concentrated. The crude residue is purified by preparative TLC (5%MeOH/DCM) to furnish 5.5 mg of ester 2. LC/MS: [M+H]⁺ 1353, R_(t)=1.49min (method 1).

Example 2 Preparation of Methylester (3)

To a solution of methylester (2, 16 mg, 0.0111 mmol) in DCM (10 mL) isadded triethylamine (10 uL), DMAP (cat.) and acetic anhydride (30 uL).The solution is stirred at RT for 2 h and concentrated. The cruderesidue is purified by preparative TLC (5% MeOH/DCM) to afford 10 mg ofproduct (3). LC/MS: [M+2H]⁺ 1438, R_(t)=1.64 min (method 1).

Example 3 Preparation of Methylester (4)

To a solution of acid (1, 200 mg, 0.149 mmol) in acetone (50 mL), andH₂O (10 mL) is added cesium carbonate (50 mg) and iodomethane (10 uL).The reaction is stirred for 12 h at RT and iodomethane (10 uL) is added,and the reaction is stirred for 12 h further. The reaction isconcentrated and purified by flash chromatography (gradient elution:0-10% MeOH/DCM) then preparative thin layer chromography (5% MeOH/DCM)which affords 5 mg of 4. LC/MS [M+2H]⁺ 1368, R_(t)=1.58 min, (method 1).

Example 4 Preparation of Chlorohydrin (5)

To a solution of acid (1, 145 mg, 0.1083 mmol) is added 50 uL ofconcentrated aq HCl (12 M). The flask is sealed, heated to 50° C., andstirred for 1 h. The reaction is concentrated and purified bypreparative TLC (10% MeOH/EtOAc) which affords 5 mg of chlorohydrin 5.LC/MS: [M+H]⁺ 1236, R_(t)=1.17 min, (method 1).

Example 5 Preparation of Epoxide (6)

To a solution of chlorohydrin (5, 100 mg, 0.0809 mmol) in MeOH (50 mL)is added sodium hydroxide (s, 50 mg) and H₂O (20 mL). The reaction isstirred at RT for 1 h and then concentrated. The crude residue ispurified by preparative TLC (10% MeOH/DCM) which affords 10 mg ofepoxide 6. LC/MS: [M+2H]⁺ 1201, R_(t)=1.10 min (method 1).

Example 6 Preparation of Amine (7)

To a suspension of chlorohydrin (5, 105 mg, 0.0848 mmol) in THF (10 mL)is added sodium perchlorate (8 mg, 0.0848 mmol) and dimethylamine (212uL, 2.0 M solution in THF, 0.424 mmol). The reaction is heated to 50° C.After 2 h, 1 eq of perchlorate and 5 eq of amine are added. The reactionis stirred for 12 h and is concentrated onto SiO₂. The crude material ispurified via flash chromatography (gradient elution: 0-10% MeOH/DCM,then 0-10% MeOH/DCM+0.1% NH₄OH) which affords 29 mg of amine 7. LC/MS:[M+H]⁺ 1245, R_(t)=0.69 min (method 1).

Example 7 Preparation of Amine (8)

Compound 8 is prepared as described in example 6. LC/MS: [M+H]⁺ 1257,R_(t)=0.82 min (method 1).

Example 8 Preparation of Amine (9)

Compound 9 is prepared as described in example 6. LC/MS: [M+H]⁺ 1285,R_(t)=0.87 min (method 1).

Example 9 Preparation of Amine (10)

Compound 10 is prepared as described in example 6. LC/MS: [M+H]⁺ 1286,R_(t)=0.79 min (method 1).

Example 10 Preparation of Pyrrolidine (11)

To a suspension of the chlorohydrin (100 mg, 0.0808 mmol) in acetone (5mL) is added ammonium hydroxide (500 uL, sat. aq). The reaction issealed and stirred for 12 h at 65° C. The reaction is concentrated andpurified by HPLC (method 1) which affords 20 mg compound 11. LC/MS:[M+H]⁺ 1094, R_(t)=0.99 min (method 1).

Example 11 Preparation of Carboxylic acid (12)

To a suspension of the chlorohydrin (5, 115 mg, 0.0929 mmol) in THF (50mL) is added sodium hydride (50 mg, 60% dispersion, 1.25 mmol) thent-butylbromoacetate (50 uL, 0.197 mmol). The reaction is stirred at RTfor 8 h and concentrated onto SiO₂. Purification by flash chromatography(gradient elution: 0-10% MeOH/DCM, then 0-10% MeOH/DCM+1% AcOH) thenHPLC (method 1) affords 10 mg compound 12. LC/MS: [M+H]⁺ 1258,R_(t)=0.81 min (method 1).

Example 12 Preparation of Pyrrolidine (13)

To a suspension of the chlorohydrin (5, 100 mg, 0.808 mmol) in THF (50mL) is added DBU (30 uL, 0.197 mmol). The reaction is stirred at RT for3 h while dissolution occurs and then is concentrated onto SiO₂.Purification by flash chromatography (gradient elution: 0-10% MeOH/DCM)affords 70 mg compound 13. LC/MS: [M+2H]⁺ 1201, R_(t)=1.10 min (method1).

Example 13 Preparation of Acid (14)

Step 1:

To a solution of the chlorohydrin (5, 200 mg, 0.162 mmol) in THF (10 mL)is added DMAP (50 mg, 0.410 mmol) and acetic anhydride (200 uL, 1.96mmol). The solution is stirred at 60° C. for 72 h and concentrated ontoSiO₂. Flash chromatography (gradient elution: 0-10% MeOH/DCM) affords 70mg of the imide triacetate. LC/MS: [M+2H]⁺ 1405, R_(t)=1.56 min. (method1).

Step 2:

To a solution of the imide-triacetate (175 mg, 0.125 mmol) in DMF (2 mL)is added alkylbromide (100 uL). The reaction is cooled to −10° C. andsodium hydride is added (50 mg, 1.25 mmol). The reaction is warmed to 0°C. and the reaction stirs for 12 h at 0° C. The reaction is diluted withH₂O and ethyl acetate. The aq. layer is extracted 3× with ethyl acetateand the combined organic extracts are washed with H₂O (5×). The organicsare dried under MgSO₄, filtered, and concentrated which affords thecrude allylimide. LC/MS: [M+2H]⁺ 1409, R_(t)=1.66 min (method 1).

Step 3:

To a solution of the crude allylimide in MeOH/DCM (50 mL, 10:1) is added50 uL of saturated aq LiOH. The reaction stirs at RT for 12 h and isconcentrated onto SiO₂. Flash chromatography (gradient elution: 0-10%MeOH/DCM+0.1% AcOH) followed by reverse phase flash chromatography(gradient elution: 20-60% MeCN/H₂O) affords 13 mg of compound 14. LC/MS:[M+H]⁺ 1201, R_(t)=1.01 min. (method 1).

Alternative synthesis (scheme 4a):Steps 1, 2:

To a mixture of compound 13a (9.5 g), DMAP (0.35 g), Ac₂O (7.2 mL) inDCM (300 mL) is added DBU (8.6 mL) and stirred at RT. When the reactionis finished (˜8 h, LC/MS), K₂CO₃ (10 g) and MeOH (300 mL) are added tothe reaction mixture. When the reaction is finished (˜16 h, LC/MS), themixture is concentrated in vacuo to dryness (bath temp <25° C.). Water(400 mL) is added and the resulting solid is filtered through a frittedglass funnel and washed with water. The filtercake is dried in vacuo for12 h to provide 9.2 g of compound 13. LC/MS: [M+H]⁺ 1200, R_(t)=1.22 min(method 13).

Step 3: Preparation of Acid (14)

To 18 g of 13 is added 94 mL of THF and 3 mL of conc. HCl in pressurebottle. The sealed bottle is heated to 100° C. and stirred for 3 days.After cooling to below 35° C., additional 2 mL of conc. HCl is added.The sealed bottle is heated to 100° C. for another two days and cooledto room temperature. The mixture is transferred into 500 mLround-bottomed-flask and 40 g of silica gel is added. Afterconcentration, the residue is divided into four portions. Flashchromatography (gradient elution: 0-20% MeOH/DCM with 1% acetic acid)affords 12 g of 14. LC/MS: [M+H]⁺ 1201, R_(t)=1.14 min (method 13).

Example 14 Preparation of Pyrrolidine (15)

To a suspension of chlorohydrin (5, 100 mg, 0.081 mmol) in THF (15 mL)is added LiClO₄ (26 mg, 0.243 mmol) and pyrrolidine (34 uL, 0.405 mmol).The reaction is stirred at 50° C. for 12 h. The reaction is cooled to RTand concentrated onto silica gel for purification by flashchromatography (gradient elution: 0-10% MeOH/DCM+0.1% ACOH) then by HPLC(30-60% acetonitrile in H₂O+0.1% TFA) furnishing 2.7 mg compound 15 asthe TFA salt. LC/MS: [M+H]⁺ 1165, R_(t)=0.67 min (method 1).

Example 15 Preparation of Piperidine (16)

Compound 16 is prepared as described in example 14. LC/MS: [M+H]⁺ 1179,R_(t)=0.74 min (method 1).

Example 16 Preparation of Aminoacid (17)

Step 1:

To a suspension of chlorohydrin (5, 100 mg, 0.081 mmol) in THF (15 mL)are added LiClO₄ (26 mg, 0.243 mmol) and methyl isonipecotate (12.7 mg,0.089 mmol). The reaction is stirred at 50° C. for 12 h. Additionalmethyl isonipecotate (11.6 mg, 0.081 mmol) is added to the reaction andstirring continues for 48 h. The reaction is cooled to RT andconcentrated onto silica gel for purification by flash chromatography(gradient elution: 0-10% MeOH/DCM). LC/MS: [M+H]⁺ 1343, R_(t)=0.96 min(method 1).

Step 2:

The crude material is dissolved in MeOH (8 mL) and DCM (5 mL) and NaOH(s, 10 mg, 0.243 mmol) is added. The reaction is stirred at 30° C. for12 h and is cooled to RT and concentrated onto silica gel forpurification by flash chromatography (gradient elution: 0-10%MeOH/DCM+1% AcOH) followed by HPLC (30-70% acetonitrile in H₂O+0.1% TFA)to afford 3.5 mg compound 17. LC/MS: [M+H]⁺ 1329, R_(t)=0.78 min (method1).

Example 17 Preparation of Amino-acid (18)

Compound 18 is prepared as described in example 16. LC/MS: [M+H]⁺ 1343,R_(t)=0.79 min (method 1).

Example 18 Preparation of Amino-piperidine (19)

Compound 19 is prepared as described in example 14. LC/MS: [M+H]⁺ 1300,R_(t)=0.71 min (method 1).

Example 19 Preparation of Pyrrolidine acid (20)

To a solution of chlorohydrin (5, 150 mg, 0.121 mmol) in DMF (10 mL) isadded K₂CO₃ (25.1 mg, 0.182 mmol). The reaction is stirred at RT for 1h, then methyl-5-bromovalerate (47.2 uL, 0.242 mmol) is added and thereaction is heated to 35° C. for 2 h. Additional K₂CO₃ (0.242 mmol) andmethyl-5-bromovalerate (47.2 uL, 0.242 mmol) is added and the reactionis stirred for 16 h. The reaction is cooled to RT and H₂O (60 mL) isadded. The resulting precipitate is filtered and dried in vacuo. Thecrude material is dissolved in MeOH (16 mL) and H₂O (4 mL). NaOH (s,19.3 mg, 0.484 mmol) is added and the reaction is stirred at RT for 12h. The reaction is concentrated onto silica gel for purification byflash chromatography (gradient elution: 0-10% MeOH/DCM+0.1% ACOH)followed by HPLC (35-70% acetonitrile in H₂O+0.1% TFA) to afford 11 mgcompound 20. LC/MS: [M+H]⁺ 1194, R_(t)=0.97 min (method 1).

Example 20 Preparation of Pyrrolidine (21)

Step 1:

To a suspension of chlorohydrin (5, 500 mg, 0.404 mmol) in MeOH (50 mL)is added excess of saturated aq LiOH (1 mL) and reaction is stirred for2 h at RT. The reaction is concentrated onto silica gel and purified byflash chromatography (gradient elution: 0-10% MeOH/DCM) to furnish 450mg of epoxide 6. LC/MS: [M+H]⁺ 1200, R_(t), 1.12 min (method 1).

Step 2:

To a suspension of the epoxide (6, 150 mg, 0.125 mmol) in EtOH (20 mL)is added excess pyrrolidine (>10 eq) and the reaction is heated to 70°C. for 16 h. The reaction is cooled to RT and concentrated onto silicagel. Purification by flash chromatography (gradient elution: 0-10%MeOH/DCM) followed by reversed phase chromatography (C18 column, 30-70%acetonitrile in H₂O with 0.1% NH₄OH) furnishes 120 mg compound 21.LC/MS: [M+H]⁺ 1271, R_(t)=0.77 min (method 1).

Example 21 Preparation of Triacetate (22)

To a solution of chlorohydrin (5, 70 mg, 0.057 mmol) in THF (10 mL) isadded acetic anhydride (100 uL) and DMAP (20 mg). The reaction isstirred at RT for 2 h and is concentrated onto silica gel and purifiedby flash chromatography (gradient elution: 0-5% MeOH/DCM) to furnish 6.6mg compound 22. LC/MS: [M+2H]⁺ 1327, R_(t)=1.36 min (method 1).

Example 22 Preparation of Pyrrolidine-alcohol (23)

Compound 23 is prepared as described in example 16. LC/MS: [M+H]⁺ 1287,R_(t)=0.69 min (method 1).

Example 23 Preparation of Propylamine (24)

To a suspension of epoxide (6, 120 mg, 0.100 mmol) in EtOH (20 mL) isadded an excess of propylamine. The reaction is heated to 70° C. in asealed tube for 16 h. The reaction is cooled to RT and concentrated ontosilica gel. Purification by flash chromatography (gradient elution:0-10% MeOH/DCM+0.1% NH₄OH) followed by HPLC (30-60% acetonitrile in H₂Owith 0.1% TFA) furnishes 5.4 mg compound 24. LC/MS: [M+H]⁺ 1259,R_(t)=0.72 min (method 1).

Example 24 Preparation of Diol (25)

To a suspension of epoxide (6, 200 mg, 0.167 mmol) in MeOH (10 mL) andDCM (20 mL) is added TFA (5 mL). The reaction is sealed and stirred atRT for 16 h. The reaction is concentrated and purified by HPLC (20-60%acetonitrile in H₂O with 0.1% TFA) to furnish 20 mg compound 25. LC/MS:[M+H]⁺ 1218, R_(t)=0.89 min (method 1).

Example 25 Preparation of Diamine (26)

Compound 26 is prepared as described in example 23. LC/MS: [M+H]⁺ 1260,R_(t)=0.67 min (method 1).

Example 26 Preparation of Amine (27)

Compound 27 is prepared as described in example 23. LC/MS: [M+H]⁺ 1261,R_(t)=0.69 min (method 1).

Example 27 Preparation of Amine (28)

Compound 28 is prepared as described in example 23. LC/MS: [M] 1230,R_(t)=0.53 min (method 1).

Example 28 Preparation of Amine (29)

To a suspension of epoxide (6, 200 mg, 0.167 mmol) in EtOH (20 mL) isadded ammonium hydroxide solution in H₂O (1:1, 1.2 mL). The reaction isheated to 60° C. in a sealed tube for 18 h. Additional ammoniumhydroxide solution (2 mL) is added and the reaction is heated to 70° C.for 12 h. The reaction is cooled to RT and concentrated onto silica gel.Purification by flash chromatography (gradient elution: 0-10%MeOH/DCM+0.1% NH₄OH) followed by HPLC (25-60% acetonitrile in H₂O with0.1% NH₄OH) furnishes 21 mg compound 29. LC/MS: [M+H]⁺ 1217, R_(t)=0.66min (method 1).

Example 29 Preparation of Methylethers (30, 31)

To a solution of pyrrolidine (13, 214 mg) in DMF (7 mL) is added cesiumbicarbonate (103 mg, 0.316 mmol), and MeI (10 μL, 0.16 mmol). Thereaction slowly progresses to 50% completion (LC/MS), and is cooled to0° C. and stored for 12 h. Upon warming to 40° C. no further reaction isobserved. Water (20 mL) is added and the resulting white precipitate isfiltered. The crude white solid is then resubjected to the aboveconditions (85% completion via LC/MS). Water (20 mL) is added to thereaction mixture, and the resulting precipitate is filtered. Excessiodomethane is removed from the crude mixture in vacuo. To a solution ofthe crude methylether in DMF (7 mL) is added acetic anhydride (200μL, >100 eq) and DMAP (cat). The reaction mixture stirs for 12 h.Pyridine (2 mL) is added to the reaction mixture, and the reaction isstirred 1 h. Water (20 mL) is added, and the resulting white precipitateis filtered. The product is purified via flash chromatography (gradientelution: 0-10% MeOH/DCM) then HPLC (40-70% acetonitrile/water+0.1%NH₄OH) to separately furnish compounds 30 and 31. Compound 30, LC/MS:[M+H]⁺ 1214, R_(t)=1.2 min (method 1). Compound 31, LC/MS: [M+H]⁺ 1256,R_(t)=1.3 min (method 1).

Example 31 Preparation of Acids (32, 33)

Step 1:

To a solution of pyrrolidine (13, 150 mg, 0.125 mmol) in DMF (2 mL) isadded cesium carbonate (50 mg, >100 eq) and 4-bromobutyric acid methylester (10 μL, >10 eq). The reaction is stirred at 35° C. for 48 h. Water(20 mL) is added and the precipitate is filtered.

Step 2:

To a solution of the ether precipitate from step 1 in a 1:1:1 solutionof THF/MeOH/water (40 mL) is added aq LiOH (4 N, 0.5 mL, >100 eq).Ammonium chloride (2 mL, saturated aq) is added to quench the reaction,and the mixture is concentrated onto silica gel. The crude mixture ispurified via flash chromatography (gradient elution: 0-10% MeOH/DCM) toseparately afford compounds 32 and 33. Compound 32 is then furtherpurified via HPLC (method 6) to furnish a white solid. LC/MS: [M+H]⁺1286, R_(t)=0.99 min (method 1). Compound 33 is further purified viaHPLC (method 1) to afford a white solid. LC/MS: [M] 1179, R_(t)=0.95 min(method 1).

Step 1:

To a suspension of pyrrolidine 13 (100 mg, 0.0833 mmol) in THF (5 mL) ina glass reinforced sealed tube is added concentrated aq HCl (12 M, 100uL). The suspension is sonicated for 5 min and sealed. The mixture isheated to 100° C. and stirs for 12 h. The mixture is mounted onto SiO₂and purified by flash chromatography (gradient elution: 0-10% MeOH/DCM)which affords 70 mg of acid 14.

Step 2:

To a solution of acid 14 (70 mg, 0.0583) in DCM (10 mL) is added N,N′-dicyclohexylcarbodiimide (92 mg, 0.1746 mmol, immobilized onpolystyrene, 1.9 mmol/g), trans-4-amino-cyclohexylcarboxylic acid methylester hydrochloride (14 mg, 0.0873 mmol), and pyridine (30 uL).Alternatively, TBTU, HATU and other amino-acid coupling conditions maybe used in the coupling reaction. The reaction is stirred for 12 h andis mounted onto SiO₂. Flash chromatography (gradient elution: 0-10%MeOH/DCM) affords 25 mg of the amide 34. LC/MS: [M+H]⁺ 1340, R_(t)=1.43min (method 1).

Step 3:

To a solution of amide 34 (25 mg, 0.0089 mmol) in DCM (10 mL) and MeOH(5 mL) is added LiOH (50 uL, saturated aq solution). The reaction stirsat RT for 6 h and is mounted onto SiO₂ and filtered through a SiO₂ plug(10% MeOH/DCM+0.1% AcOH) which results in the recovery of 18 mg of crudeacid. The crude acid is then purified via preparatory TLC (10% MeOH/DCM)which affords 8 mg of acid 35. LC/MS: [M+H]⁺=1326, R_(t)=1.17 min(method 1).

Example 33 Preparation of Acid (36)

Compound 36 is prepared as described in scheme 5 and example 29. LC/MS:[M+H]⁺ 1215, R_(t)=1.24 min (method 1).

Example 34 Preparation of Amines (37, 38)

Step 1:

To a solution of the pyrrolidine (13, 300 mg, 0.20 mmol) in DMF (10 mL)at 0° C. is added 2-(boc-amino) ethyl bromide (224 mg, 1.0 mmol) thenCs₂CO₃ (800 mg, 2.5 mmol). The reaction is allowed to warm to RT. ExcessCs₂CO₃ (800 mg, 2.5 mmol) and 2-(boc-amino) ethyl bromide (224 mg, 1.0mmol) are added. Water (100 mL) is added and the products are collectedvia filtration.

Step 2:

To a solution of the crude boc protected amine (contaminated with thebenzaldehyde elimination byproduct) in DCM (30 mL) is added TFA (5 mL).Upon completion of the deprotection, the mixture is concentrated ontosilica gel and purified via flash chromatography (gradient elution 0-10%MeOH/DCM, then 2% NH₄OH, in 15% MeOH/DCM.). Final purification isperformed via HPLC yielding 37, LC/MS: [M+H]⁺ 1243, R_(t)=0.8 min(method 1), and 38, LC/MS [M+H]⁺ 1137, R_(t)=0.7 min (method 1).

Example 35 Preparation of Acid (39)

Compound 39 is prepared as described in scheme 5. LC/MS: [M+2H]⁺ 1341,R_(t)=1.1 min (method 1).

Example 36 Preparation of Amino-ester (40)

Compound 40 is prepared as described in scheme 5 and example 34. LC/MS:[M+2H]⁺ 1454, R_(t)=1.1 min (method 1).

Example 37 Preparation of Ester (41)

Compound 41 is prepared as described in scheme 5. LC/MS: [M+2H]⁺ 1355,R_(t)=1.3 min (method 1).

Example 38 Preparation of Acid (42)

Compound 42 is prepared as described in scheme 5. LC/MS: [M+H]⁺ 1234,R_(t)=1.05 min (method 1).

Example 39 Preparation of Acid (43)

Compound 43 is prepared as described in scheme 5. LC/MS: [M+H]⁺ 1220,R_(t)=0.98 min (method 1).

Example 40 Preparation of amines (44, 45)

Compounds 44, 45 are prepared as described in example 34. Compound 44:LC/MS [M+H]⁺ 1299, R_(t)=0.9 min (method 1) Compound 45: LC/MS [M+H]⁺1193, R_(t)=0.8 min (method 1).

Example 41 Preparation of Amino-acid (46)

Compound 46 is prepared as described in scheme 5 and in example 34.LC/MS: [M+H]⁺ 1425, R_(t)=0.94 min (method 1).

Example 42 Preparation of Amino-acid (47)

Compound 47 is prepared as described in scheme 5 and in example 34.LC/MS: [M+H]⁺ 1319, R_(t)=0.92 min (method 1).

Example 43 Preparation of Amino-acid (48)

Compound 48 is prepared as described in scheme 5 and in example 34.LC/MS: [M] 1418, R_(t)=0.96 min (method 1).

Example 44 Preparation of Bromoacids (49, 50)

Step 1:

To a sonicated, −78° C. THF suspension of ester (100 mg compound 34 in10 mL THF) is added 100 uL of bromine solution (prepared by adding 20 uLbromine to 1 mL DCM). The reaction is monitored by LC/MS and is quenchedat −78° C. by adding 1 g of SiO₂. The solvents are removed in vacuo andthe crude material is eluted with 10% MeOH in DCM. The crude material (amixture of mono and di-brominated products) is carried on with nofurther purification.

Step 2:

To a solution of the crude bromination products (20 mL, 1:1 DCM/MeOH) isadded LiOH (1 mL sat'd aq solution). The reaction stirs at RT for 6 hand is concentrated onto SiO₂ and is eluted with 10% MeOH in DCM+1%AcOH. The products are purified via HPLC (gradient elution: 55%-65%MeCN/H₂O+0.1% TFA). Compound 49: LC/MS: [M+3H]⁺ 1406, R_(t)=1.17 min(method 1). Compound 50: LC/MS: [M+5H]⁺ 1486, R_(t)=1.22 min (method 1).

Example 45 Preparation of Tetrazole (51)

Compound 51 is prepared as described in scheme 5 and in example 34.LC/MS: [M+3H]⁺ 1410, R_(t)=0.86 min (method 1).

Example 46 Preparation of Nitroacid (52)

Step 1:

To a solution of the ester (34, 200 mg) in AcOH (5 mL) is added 300 uLof 60% nitric acid. The reaction stirs for 20 min, 1 mL of sat'd aqbicarbonate solution is added, and 1 g of SiO₂. The solvents are removedin vacuo and the crude product is eluted through a short silica plugwith 10% MeOH in DCM. The solvents are removed in vacuo and the crudenitro-ester is taken on with no further purification.

Step 2:

100 mg of the crude nitro ester is dissolved in MeOH/DCM (5 mL, 1:1) andLiOH sat'd aq solution is added (150 uL). After 5 h, 1 g SiO₂ is addedand the solvents are removed in vacuo. The crude mixture is elutedthrough a short silica plug with 10% MeOH in DCM+1% AcOH. The solventsare removed in vacuo and the crude nitro-acid is purified via HPLC(gradient elution: 55%-80% MeCN/H₂O+0.1% TFA). LC/MS: [M+2H]⁺ 1372,R_(t)=1.16 min (method 1).

Example 47 Preparation of Aniline-acid (53)

Step 1:

To a solution (10 mL DCM/MeOH, 1:1) of the nitro-ester (as prepared inexample 46) is added 100 mg of Pd/C (10%). The suspension is evacuatedof dissolved gases and backfilled with hydrogen via balloon (3×). Thereaction is stirred at RT for 48 h and monitored by LC/MS. The mixtureis then filtered though a pad of Celite (10% MeOH/DCM) and the resultingwhite solid is taken on to the next step with no further purification.

Step 2:

The crude ester is dissolved in 10 mL MeOH/DCM (2:1) and LiOH is added(150 uL sat'd aq solution). After 5 h of stirring at RT, the reaction isconcentrated onto SiO₂ and eluted through a short silica plug with 10%MeOH/DCM+1% AcOH. The crude material is then purified by HPLC (gradientelution: 20-60% MeCN/H₂O+0.1% TFA). LC/MS: [M+3H]⁺ 1343 (method 1),R_(t)=11.86 min (LC).

Example 48 Preparation of Aniline (54)

Compound 54 is prepared from pyrrolidine 13 according to the proceduresdescribed in example 47. LC/MS: [M+H]⁺ 1215, R_(t)=1.07 min (method 1).

Example 49 Preparation of Alcohol (55)

Compound 55 is prepared from compound 54 by dissolving the aniline inpyridine (200 mg in 10 mL) and adding 100 mg of TBTU and 25 mg ofglycolic acid. The reaction stirs for 3 h at RT and is concentrated ontoSiO₂. The crude alcohol is purified by flash chromatography (gradientelution 0-10% MeOH in DCM) and then HPLC (gradient elution: 35-55% MeCNin H₂O+0.1% TFA). LC/MS: [M+H]⁺ 1273, R_(t)=1.02 min (method 1).

Example 50 Preparation of Guanidine-acid (56)

Step 1:

To a solution of compound 34 (1.0 g, 0.75 mmol) in DCM/DMF (5:1, 120 mL)is added acetic anhydride (0.5 mL, 10 eq) and DMAP (cat.). The DCM isremoved under vacuum, and the product is precipitated upon addition ofwater (400 mL) to give the intermediate triacetate as an orange solid(780 mg). The triacetate is dissolved in DCM (2 mL). MeOH is added (20mL), followed by HCl (conc. 100 μL). The reaction is concentrated ontosilica gel, and purified via flash chromatography (gradient elution 0-5%MeOH/DCM) to provide a mixture of diacetate and starting material (1:1,400 mg). [M+H]⁺ 1424, R_(t)=1.44 (method 1).

Step 2:

To a solution of the diacetate (600 mg, 0.42 mmol) in DMF is added3-(boc-amino)propyl bromide (1.0 g, 4.22 mmol) and cesium carbonate (1.4g, 4.22 mmol). The reaction is stirred for 12 h. The mixture isconcentrated onto silica gel and purified via flash chromatography(gradient elution 0-10% MeOH/DCM). To a solution of this crude mixturein DCM (20 mL) is added acetic anhydride (0.5 mL, >100 eq) and DMAP(cat). The solution is concentrated and placed under vacuum providingthe boc-amino-diacetate.

Step 3:

To a solution of the intermediate boc-amino-diacetate in DCM (10 mL) isadded TFA (1 mL). After 1 hr the solution is concentrated onto silicagel and purified via flash chromatography (gradient elution 0-10%MeOH/DCM) to provide amino-diacetate (200 mg).

Step 4:

To a solution of amino-diacetate (200 mg, 0.14 mmol) in DCM (10 mL) isadded DIEA (0.5 mL) and 1-amidinopyrazol monohydrochloride (120 mg, 1.1mmol). After the reaction is complete, DCM (10 mL), MeOH (10 mL), water(3 mL) and LiOH (4 mL) are added. The solution is concentrated ontosilica gel and purified via flash chromatography (gradient elution 0-10%MeOH/DCM), HPLC, then preparative TLC (10% MeOH/DCM). LC/MS: [M+H]⁺1425, R_(t)=0.82 (method 1).

Example 51 Preparation of Tetrazole (57)

Compound 57 is prepared according to the procedures described in example34. LC/MS: [M+H]⁺ 1282, R_(t)=0.84 (method 1).

Example 52 Preparation of Morpholine (58)

Compound 58 is prepared according to the procedures described in example34. LC/MS: [M+H]⁺ 1313, R_(r)=1.00 (method 1).

Example 53 Preparation of Imidazole (59)

Compound 59 is prepared according to the procedures described in example34. LC/MS: [M+H]⁺ 1280, R_(t)=0.92 (method 1).

Example 54 Preparation of Pyrrolidine (60)

Compound 60 is prepared according to the procedures described in example49. LC/MS: [M+2H]⁺ 1341, R_(t)=0.91 (method 1).

Example 55 Preparation of Piperidine (61)

Compound 61 is prepared according to the procedures described in example34. LC/MS: [M+H]⁺ 1311, R_(t)=0.90 (method 1).

Example 56 Preparation of Amine (62)

To a solution of compound 14 (300 mg, 0.25 mmol) in pyridine (10 mL) isadded piperazine hydrochloride (108 mg, 1.25 mmol) and TBTU (160 mg,0.50 mmol). The solution is stirred for 12 h, then concentrated ontosilica gel and purified via flash chromatography (gradient elution 0-20%MeOH/DCM with 1% NH₄OH). Final purification via HPLC provides compound62. LC/MS: [M+2H]⁺ 1270, R_(t)=0.85 min (method 1).

Example 57 Preparation of Amine (63)

Compound 63 is prepared as described in example 56. LC/MS: [M+2H]⁺ 1314,R_(t)=0.92 min (method 1).

Example 58 Preparation of Amine (64)

Compound 64 is prepared as described in example 56. LC/MS: [M+2H]⁺ 1256,R_(t)=1.1 min (method 1).

Example 59 Preparation of Amine (65)

Compound 65 is prepared as described in example 56. LC/MS: [M+2H]⁺ 1338,R_(t)=1.0 min (method 1).

Example 60 Preparation of Acid (66)

To a solution of pyrrolidine 13 (100 mg in 80 mL DCM, 20 mL MeOH, 5 mLH₂O) is added 2 mL of saturated aq LiOH. The reaction is stirred at RTfor 4 h. NaOH is added (50 mg, s), and the reaction stirs 12 h. Thereaction is heated to 40° C. for 3 h and is concentrated onto SiO₂ andpurified by flash chromatography (gradient elution: 0-10% MeOH/DCM+0.1%AcOH) then HPLC (gradient elution: 30-60% MeCN in H₂O+0.1% TFA). LC/MS:[M+H]⁺ 1095, R_(t)=0.94 min (method 1).

Example 61 Preparation of Acids (69, 70)

Step 1:

To a solution of compound 13 (400 mg, 0.333 mmol) in pyridine (0.54 mL)and DMF (40 mL), is added acetic anhydride (34.6 uL, 0.366 mmol). Thereaction mixture is stirred at 0° C. for 3 h, and the reaction isquenched by MeOH. The reaction mixture is concentrated and the residueis purified by flash chromatography, (gradient elution: 0-10% MeOH/DCM)to provide the desired monoacetate 66a. LC/MS: [M+2H]⁺ 1243, R_(t)=0.61(method 14).

Step 2:

To a solution of compound 66a (100 mg, 0.08 mmol) in DMF (0.7 mL), isadded DMAP (19.7 mg, 0.161 mmol) and CDI (39 mg, 0.24 mmol). Thereaction mixture is stirred at RT for 3 h. Pyridine is then added (0.08mL) followed by the amine (47.5 mg, 0.24 mmol). The reaction is stirredat RT for 12 h. The reaction mixture is concentrated, the residue ispurified by flash chromatography, eluting with MeOH/DCM (0-10%) toprovide compound 67 and compound 68. 67: LC/MS: [M+NH₄]⁺1445, R_(t)=1.43min. 68: LC/MS: [M+NH₄]⁺1445, R_(t)=1.41 min (method 14).

Step 3:

To a solution of compound 67 (100 mg, 0.070 mmol) in DMF (3 mL), isadded concentrated HCl (4 mL) and 4N HCl/dioxane (4 mL). The reaction isstirred at RT for 12 h. The reaction mixture is concentrated, and theresidue is purified by HPLC (neutral conditions) to provide compound 69.LC/MS: [M+2H]⁺ 1330, R_(t)=1.21 min. Compound 68 (80 mg, 0.056 mmol) isdissolved in DMF (2 mL) and concentrated HCl (1.5 mL), 4N HCl/Dioxane (3mL) and 3 drops of H₂O. The reaction is stirred at RT for 12 h. Thereaction mixture is concentrated, and the residue is purified by HPLC(neutral condition) to provide compound 70. LC/MS: [M+2H]⁺ 1330,R_(t)=1.19 min (method 14).

Example 62 Preparation of Urethanes (71, 72)

Step 1:

To a solution of the amide (13, 716 mg, 0.596 mmol) in methanol (6.4 mL)and dichloromethane (57 mL) are added N,N-diisopropylethylamine (1.04mL, 5.96 mmol) and trimethylsilyldiazomethane (2 M in ether, 3.00 mL,5.96 mmol) dropwise. The resulting mixture is stirred at RT for 12 h andthen concentrated under reduced pressure. The resulting residue istreated with dichloromethane (100 mL) and filtered to provide a whitesolid of the methyl ether (720 mg). LC/MS: [M+H]⁺ 1214, R_(t)=1.28 min(method 13).

Step 2:

To a solution of the methyl ether (106 mg, 0.0873 mmol) in N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (76 uL, 0.437 mmol) andethyl isocyanate (10 uL, 0.131 mmol) is added1,8-diazabicyclo[5.4.0]undec-7-ene (13 uL, 0.0873 mmol) dropwise at 0°C. After 30 min at 0° C., methanol (0.5 mL) is added and thenconcentrated under reduced pressure. The residue is purified viaprep-TLC (10% MeOH/DCM) and HPLC to provide compound 71 and compound 72.Compound 71: LC/MS: [M+H]⁺ 1285, R_(t)=1.32 min (method 13). Compound72: LC/MS: [M+H]⁺ 1285, R_(t)=1.31 min (method 13).

Example 63 Preparation of Acids (73, 74)

Compounds 73 and 74 are prepared as described in example 61. Compound73: LC/MS: [M+2H]⁺ 1302, R_(t)=1.19 min (method 14). Compound 74: LC/MS:[M+2H]⁺ 1302, R_(t)=1.17 min (method 14).

Example 64 Preparation of Amine (75)

Compound 75 is prepared as described in example 61. LC/MS: [M+H]⁺ 1356,R_(t)=1.22 min (method 13).

Example 65 Preparation of Amines (76, 77)

Compounds 76, 77 are prepared as described in example 61. Compound 76:LC/MS: [M+2H]⁺ 1313, R_(t)=1.10 min (method 13). Compound 77: LC/MS:[M+H]⁺ 1312, R_(t)=1.04 min (method 13).

Example 66 Preparation of Urethane (78)

Compound 78 is prepared as described in example 61. Compound 78: LC/MS:[M+H]⁺ 1271, R_(t)=1.11 min (method 13).

Example 67 Preparation of Acid (79)

Compound 79 is prepared according to scheme 5. LC/MS: [M+2H]⁺ 1287,R_(t)=1.20 min (method 14).

Example 68 Preparation of Acid (80)

Compound 80 is prepared according to scheme 5. LC/MS: [M+2H]⁺ 1316,R_(t)=1.15 min (method 14).

Example 69 Preparation of Acid (81)

Compound 81 is prepared according to scheme 5. LC/MS: [M+2H]⁺ 1374,R_(t)=1.17 min (method 14).

Example 70 Preparation of Acid (82)

Compound 82 is prepared according to scheme 5. LC/MS: [M+2H]⁺ 1374,R_(t)=1.17 min (method 14).

Example 71 Preparation of Acid (83)

Compound 83 is prepared according to scheme 5. LC/MS: [M+H]⁺ 1300,R_(t)=1.24 min (method 14).

Example 72 Preparation of Acid (84)

Compound 84 is prepared according to scheme 5. LC/MS: [M+2H]⁺ 1259,R_(t)=1.20 min (method 14).

Example 73 Preparation of Acid (85)

Compound 85 is prepared according to scheme 5. LC/MS: [M+2H]⁺ 1315,R_(t)=1.27 min (method 14).

Example 74 Preparation of Acid (86)

Compound 86 is prepared according to scheme 5. LC/MS: [M+2H]⁺ 1327,R_(t)=1.27 min (method 14).

Example 75 Preparation of Amine (87)

Compound 87 is prepared according to example 56. LC/MS: [M+2H]⁺ 1381,R_(t)=1.09 min (method 13).

Example 76 Preparation of Amine (88)

Compound 88 is prepared according to example 61. LC/MS: [M+H]⁺ 1340,R_(t)=0.99 min (method 14).

Example 77 Preparation of Amine (89)

Compound 89 is prepared according to example 61. LC/MS: [M+2H]⁺ 1371,R_(t)=1.00 min (method 14).

Example 78 Preparation of Amine (90)

Compound 90 is prepared according to example 56. LC/MS: [M+3H]⁺ 1368,R_(t)=1.07 min (method 13).

Example 79 Preparation of Amine (91)

Compound 91 is prepared according to example 56. LC/MS: [M+3H]⁺ 1385,R_(t)=0.99 min (method 13).

Example 80 Preparation of Amine (92)

Compound 92 is prepared according to example 61. LC/MS: [M+H]⁺ 1337,R_(t)=1.00 min (method 14).

Example 81 Preparation of Amine (93)

Compound 93 is prepared according to example 61. LC/MS: [M+2H]⁺ 1287,R_(t)=0.96 min (method 14).

Example 82 Preparation of Diamine (94)

Compound 94 is prepared according to the procedures described inexamples 56 and 61. LC/MS: [M+3H]⁺ 1427, R_(t)=0.80 min (method 14).

Example 83 Preparation of Diol (95)

Compound 95 is prepared according to the procedures described in example61. LC/MS: [M+H]⁺ 1317, R_(t)=1.15 min (method 14).

Example 84 Preparation of Diamine (96)

Compound 96 is prepared according to the procedures described inexamples 56 and 47. LC/MS: [M+3H]⁺ 1286, R_(t)=0.85 min (method 14).

Example 85 Preparation of Diamine (97)

Compound 97 is prepared according to the procedures described inexamples 61 and 47. LC/MS: [M+3H]⁺ 1373, R_(t)=0.93 min (method 14).

Example 86 Preparation of Polyol (98)

Compound 98 is prepared according to the procedures described in example56. LC/MS: [M+3H]⁺ 1364, R_(t)=1.07 min (method 13).

Example 87 Preparation of Alcohol (100)

Step 1:

To a solution of acid 14 (650 mg, 0.5410 mmol) in DCM (50 mL) and MeOH(50 mL) is added 12N HCl (aq) (3.0 mL). The mixture stirs at ambienttemperature 12 h. The mixture is mounted onto SiO₂ and purified by flashchromatography (gradient elution: 0-100% Acetone/DCM) which affords 410mg of methyl ester 99. LC/MS: [M+2H]⁺ 1216, R_(t)=1.34 min (method 13).

Step 2:

To a solution of methyl ester 99 (410 mg, 0.3373 mmol) in anhydrous THF(50 mL) at 0° C. is added LiBH₄ mg, 3.373 mmol). The reaction stirs atRT for 12 h and is mounted onto SiO₂ and purified (10% MeOH/DCM) whichaffords 550 mg of alcohol 100. LC/MS: [M+2H]⁺ 1188, R_(t)=1.22 min(method 13).

Example 88 Preparation of Amine (101)

Compound 101 is prepared according to the procedures described inexample 56. LC/MS: [M+3H]⁺ 1383, R_(t)=1.03 min (method 13).

Example 89 Preparation of Amide (102)

Compound 102 is prepared according to the procedures described inexample 56. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.08 (m, 4 H) 1.59 (m, 1 H)1.89 (m, 1 H) 2.19 (m, 1 H) 2.33 (m, 1 H) 2.56 (m, 2 H) 2.70 (m, 5 H)2.95 (m, 2 H) 3.23 (m, 4 H) 3.51 (m, 93 H) 3.78 (m, 1 H) 3.88 (m, 1 H)4.17 (m, 1 H) 4.69 (m, 1 H) 5.02 (m, 1 H) 5.16 (m, 1 H) 5.31 (m, 1 H)5.45 (m, 1 H) 6.35 (m, 1 H) 6.60 (m, 2 H) 6.69 (m, 1 H) 6.92 (m, 2 H)7.03 (m, 2 H) 7.23 (m, 4 H) 7.36 (m, 1 H) 7.62 (m, 1 H) 8.22 (m, 1 H)8.27 (m, 1 H) 8.43 (m, 2 H) 8.50 (m, 2 H) 8.62 (m, 2 H) 8.81 (m, 1 H)9.16 (m, 1 H).

Example 90 Preparation of Amine (103)

Compound 103 is prepared according to the procedures described inexample 61 and scheme 5. LC/MS: [M+3H]⁺ 1484, R_(t)=0.96 min (method14).

Example 91 Preparation of Polyol (104)

Compound 104 is prepared according to the procedures described inexample 56. LC/MS: [M+2H]⁺ 1365, R_(t)=1.10 min (method 13).

Example 92 Preparation of Polyol (105)

Compound 105 is prepared according to the procedures described inexample 56. LC/MS: [M+3H]⁺ 1348, R_(t)=1.10 min (method 14).

Example 93 Preparation of Aminoacid (106)

Compound 106 is prepared according to the procedures described inexample 61 and scheme 5. LC/MS: [M+3H]⁺ 1484, R_(t)=1.04 min (method14).

Example 94 Preparation of Acid (107)

Compound 107 is prepared according to the procedures described inexample 61 and scheme 5. LC/MS: [M+2H]⁺ 1428, R_(t)=1.24 min (method14).

Example 95 Preparation of Acid (108)

Compound 108 is prepared according to the procedures described inexample 61 and scheme 5. LC/MS: [M+H]⁺ 1528, R_(t)=1.22 min (method 14).

Example 96 Preparation of Diacid (109)

Step 1:

To a solution of trans-4-aminocyclohexane carboxylic acid hydrochloride(5.0 g, 34.92 mmol) in aqueous 2.0N NaOH (35 mL) is added benzylchloroformate (5.0 mL, 34.92 mmol). The mixture stirs for 1.5 h. Thenthe suspension is acidified with 12N HCl (aq) to pH=1. H₂O is added (100mL) and the precipitate is filtered off. The filter cake is dried toafford 8.2 g of 4-benzyloxycarbonylamino-cyclohexanecarboxylic acid.LC/MS: [M+H]⁺=278, R_(t)=0.85 min (method 6)

Step 2:

To a solution of 4-benzyloxycarbonylamino-cyclohexanecarboxylic acid(8.0 g, 28.78 mmol) in DCM (35 mL) and DMF (35 mL) is added t-butanol(10 mL, 105.4 mmol) and DMAP (1.4 g, 11.50 mmol). DIPC (10 mL) is addedportionwise over 1 h. The resulting mixtures stirs 18 h. The mixture ismounted onto SiO₂ and purified by flash chromatography (gradientelution: 0-60% EtOAc/Hep) which affords 5.2 g of4-benzyloxycarbonylamino-cyclohexanecarboxylic acid tert-butyl ester. ¹HNMR (400 MHz, DMSO-D6) δ ppm 1.14 (m, 2 H) 1.30 (m, 2 H) 1.38 (m, 9 H)1.82 (m, 4 H) 2.07 (m, 1 H) 3.20 (m, 1 H) 3.47 (m, 3 H) 4.99 (m, 2 H)7.27 (m, 5 H).

Step 3:

To a solution of 4-benzyloxycarbonylamino-cyclohexanecarboxylic acidtert-butyl ester (3.0 g, 9.009 mmol) in THF (80 mL) is added TEA (0.24mL, 1.724 mmol) and 10% Pd/C (wet) (420 mg). The mixture stirs under ablanket of hydrogen gas at atmospheric pressure for 12 h. The mixture isthen filtered though celite. The celite is washed with MeOH (50 mL). Thefiltrated is concentrated to afford 1.8 g of4-amino-cyclohexanecarboxylic acid tert-butyl ester. LC/MS: [M+H]⁺ 200,R_(t)=0.39 min (method 6).

Step 4:

To a solution of 4-amino-cyclohexanecarboxylic acid tert-butyl ester(500 mg, 2.500 mmol) in MeOH (3 mL) is added TEA (140 uL, 1.000 mmol),MgSO₄ (452 mg, 3.750 mmol), and benzaldehyde (278 uL, 2.750 mmol). Themixture stirs 1 h. The mixture is then cooled to 0° C. and NaBH₄ (568mg, 15.00 mmol) is added portionwise over 10 min. The mixture stirs 1 hat ambient temperature. Then H₂O (20 mL) is added and the mixture isextracted with EtOAc (2×50 mL), dried and concentrated to affords 730 mgof 4-benzylamino-cyclohexanecarboxylic acid tert-butyl ester. LC/MS:[M+H]⁺ 290, R_(t)=0.80 min (method 6).

Step 5:

To a solution of 4-benzylamino-cyclohexanecarboxylic acid tert-butylester (630 mg, 2.180 mmol) in DMF (20 mL) is added t-butyl bromoacetate(1 mL, 6.856 mmol) and Cs₂CO₃ (1.0 g, 3.069 mmol). The mixture stirs for2 h. Then H₂O (50 mL) is added the mixture is extracted with EtOAc(2×100 mL), dried with sodium sulfate and concentrated. The resultingsolid is purified by flash chromatography (gradient elution: 0-20%EtOAc/Hep) which affords 300 mg of4-(benzyl-tert-butoxycarbonylmethyl-amino)-cyclohexanecarboxylic acidtert-butyl ester. ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.24 (m, 5 H), 1.38(m, 18 H), 1.86 (m, 4 H), 2.09 (m, 1 H), 3.14 (m, 2 H), 3.71 (m, 2 H),7.29 (m, 5 H).

Step 6:

To a solution of4-(benzyl-tert-butoxycarbonylmethyl-amino)-cyclohexanecarboxylic acidtert-butyl ester (300 mg, 0.7433 mmol) in EtOH (10 mL) is added 10% Pd/C(wet) (40 mg). The mixture stirs under a blanket of hydrogen gas atatmospheric pressure for 12 h. The mixture is then filtered thoughcelite. The celite is washed with MeOH (50 mL). The filtrated isconcentrated to afford 243 mg of4-(tert-butoxycarbonylmethyl-amino)-cyclohexanecarboxylic acidtert-butyl ester. ¹H NMR (400 MHz, DMSO-D6) δ ppm 0.98 (m, 2 H), 1.25(m, 2 H), 1.36 (m, 9 H), 1.41 (m, 9 H), 1.81 (m, 4 H), 2.05 (m, 1 H),2.28 (m, 1 H), 3.20 (m, 2 H).

Step 7:

To a solution of acid 14 (100 mg, 0.083 mmol) in DMF (10 mL) is added4-(tert-butoxycarbonylmethyl-amino)-cyclohexanecarboxylic acidtert-butyl ester (40 mg, 0.125 mmol), DIPEA (45 uL, 0.250 mmol), andHATU (63 mg, 0.166 mmol). The mixture stirs 12 h. The mixture is mountedonto SiO₂ and purified by flash chromatography (gradient elution: 0-7%MeOH/DCM) which affords 75 mg of the diester. LC/MS: [M+H]⁺ 1498,R_(t)=1.64 min (method 13).

Step 8:

To a solution of the diester (75 mg, 0.0501 mmol) in DCM (2 mL) is addedTFA (2 mL). The mixture stirs 1 h. Then DCM is removed under reducedpressure and the resulting oil is purified via HPLC (method 1) to afford25.6 mg of compound 109. LC/MS: [M+2H]⁺ 1385, R_(t)=1.08 min (method13).

Example 97 Preparation of Diacid (110)

Compound 110 is prepared according to the procedures described inexample 96. LC/MS: [M+2H]⁺ 1267, R_(t)=1.00 min (method 13).

Example 98 Preparation of Diacid (111)

Compound III is prepared according to the procedures described inexample 96. LC/MS: [M+3H]⁺ 1374, R_(t)=1.21 min (method 14).

Example 99 Preparation of Diacid (112)

Compound 112 is prepared according to the procedures described inexample 96. LC/MS: [M+2H]⁺ 1427, R_(t)=1.10 min (method 13).

Example 100 Preparation of Diacid (113)

Compound 113 is prepared according to the procedures described inexample 96. LC/MS: [M+3H]⁺ 1456, R_(t)=1.18 min (method 13).

Example 101 Preparation of Diacid (114)

Compound 114 is prepared according to the procedures described inexample 96. LC/MS: [M+H₃O]⁺1390, R_(t)=1.14 min (method 13).

Example 102 Preparation of Diacid (115)

Compound 115 is prepared according to the procedures described inexample 96. LC/MS: [M+3H]⁺ 1458, R_(t)=1.30 min (method 13).

Example 103 Preparation of Diacid (116)

Compound 116 is prepared according to the procedures described inexample 96. LC/MS: [M+2H]⁺ 1371, R_(t)=1.13 min (method 13).

Example 104 Preparation of Diacid (117)

Compound 117 is prepared according to the procedures described inexample 96. LC/MS: [M+2H]⁺ 1469, R_(t)=1.07 min (method 13).

Example 105 Preparation of Diacid (118)

Compound 118 is prepared according to the procedures described inexample 96. LC/MS: [M+2H]⁺ 1321, R_(t)=1.06 min (method 13).

Example 106 Preparation of Diacid (119)

Compound 119 is prepared according to the procedures described inexample 96. LC/MS: [M+2H]⁺ 1427, R_(t)=1.21 min (method 13).

Example 107 Preparation of Diacid (120)

Compound 120 is prepared according to the procedures described inexample 96. LC/MS: [M+2H]⁺ 1413, R_(t)=1.12 min (method 13).

Example 108 Preparation of Diacid (121)

Compound 121 is prepared according to the procedures described inexample 96. LC/MS: [M+2H]⁺ 1429, R_(t)=1.09 min (method 13).

Example 109 Preparation of Diacid (122)

Step 1:

To a solution of trans-4-amino-cyclohexylcarboxylic acid methyl esterhydrochloride (4.5 g, 23.24 mmol) in MeOH (30 mL) is added TEA (1.3 mL,9.339 mmol), MgSO₄ (4.2 g, 34.88 mmol), and benzaldehyde (2.5 mL, 24.74mmol). The mixture stirs 1 h. The mixture is then cooled to 0° C. andNaBH₄ (5.0 g, 132.2 mmol) is added portionwise over 0.5 h. The mixturestirs 1 h at ambient temperature. Then H₂O (200 mL) is added and themixture is extracted with EtOAc (2×500 mL), dried and concentrated. Theresulting solid is purified by flash chromatography (gradient elution:0-100% EtOAc/Hep) which affords 2.7 g of4-benzylamino-cyclohexanecarboxylic acid methyl ester. LC/MS: [M+H]⁺248, R_(t)=0.82 min (method 11).

Step 2:

To a solution of amine 4-benzylamino-cyclohexanecarboxylic acid methylester (1.4 g, 5.645 mmol) in DMSO (3 mL) is added K₂CO₃ (1.5 g, 11.29mmol) and methyl 5-bromovalerate (1.6 mL, 11.29 mmol). The mixture stirs24 h, then H₂O (20 mL) is added and the mixture is extracted with EtOAc(2×100 mL). The organic solution is washed with aqueous sat. sodiumchloride solution (100 mL), dried and concentrated. The resulting solidis purified by flash chromatography (gradient elution: 0-5% MeOH/DCM)which affords 960 mg of4-[benzyl-(4-methoxycarbonyl-butyl)-amino]-cyclohexanecarboxylic acidmethyl ester. LC/MS: [M+H]⁺ 362, R_(t)=0.78 min (method 9).

Step 3:

To a solution of amine4-[benzyl-(4-methoxycarbonyl-butyl)-amino]-cyclohexanecarboxylic acidmethyl ester (950 mg, 2.628 mmol) in MeOH (40 mL) is added 10% Pd/C(wet) (135 mg). The mixture stirs under a blanket of hydrogen gas atatmospheric pressure for 12 h. The mixture is then filtered thoughcelite. The celite is washed with MeOH (50 mL). The filtrated isconcentrated to afford 760 mg of amine4-(4-methoxycarbonyl-butylamino)-cyclohexanecarboxylic acid methylester. LC/MS: [M+H]⁺ 272, R_(t)=0.60 min (method 9).

Step 4:

To a solution of acid 14 (1.29 g, 1.073 mmol) in DMF (25 mL) is addedamine amine 4-(4-methoxycarbonyl-butylamino)-cyclohexanecarboxylic acidmethyl ester (437 mg, 1.609 mmol), DIPEA (0.573 mL, 3.219 mmol), andHATU (815 mg, 2.146 mmol). The mixture stirs 12 h. The mixture ismounted onto SiO₂ and purified by flash chromatography (gradientelution: 0-7.5% MeOH/DCM) which affords 700 mg of the diester. LC/MS:[M+2H]⁺ 1455, R_(t)=1.45 min (method 13).

Step 5:

To a solution of the diester (400 mg, 0.2750 mmol) in anhydrous DMF (10mL) is added DIPEA (0.24 mL, 1.348 mmol), DMAP (34 mg, 0.2782 mmol), andCDI (102 mg, 0.6289 mmol). The mixture stirs for 3 h, then3,4-(2-aminoethyl)morpholine (400 mg, 3.072 mmol) is added and theresulting mixture is stirred 12 h. The reaction mixture is concentratedunder reduced pressure to remove DMF and the residue is treated withwater (100 mL) and stirred 10 min. The suspension is filtered and thefiltercake is purified via preparatory TLC (10% MeOH/DCM) which affords25 mg of the urethane. LC/MS: [M+3H]⁺ 1612, R_(t)=1.12 min (method 14).

Step 6:

To a solution of the urethane-diester (25 mg, 0.0155 mmol) in DCM (1 mL)and MeOH (1 mL) is added 4.0N LiOH (aq) (0.4 mL, 0.100 mmol). Thereaction stirs at RT for 1 h and the resulting diacid is purified viaHPLC (method 1) and treated with 12NCl (aq) (0.5 mL) to afford compound122. LC/MS: [M+3H]⁺ 1584, R_(t)=1.14 min (method 13).

Example 110 Preparation of Diacid (123)

Compound 123 is prepared according to the procedures described inexample 96. LC/MS: [M+2H]⁺ 1461, R_(t)=1.17 min (method 13).

Example 111 Preparation of Acid (124)

Compound 124 is prepared according to the procedures described inexample 96. LC/MS: [M+H]⁺ 1503, R_(t)=1.24 min (method 13).

Example 112 Preparation of Acid (127)

Step 1:

To a solution of alcohol 100 (260 mg, 0.219 mmol) in DMF (5 mL) is addedDIPEA (390 uL, 2.19 mmol), CDI (64 mg, 0.394 mmol) and DMAP (26 mg,0.219 mmol). The mixture stirs at RT for 2.5 h. Then 6-amino-hexanoicacid tert-butyl ester (410 mg, 0.219 mmol, Syn. Commun. 2004, 34, 2415)is added and the resulting mixture stirs at RT for 18 h. The mixture isthen purified via preparatory TLC (10% EtOH/DCM) to yield the ester 126.LC/MS: [M+H₃O]⁺1418, R_(t)=1.52 min (method 13).

Step 2:

To the t-butyl ester (126) is added 4N HCl in 1,4-dioxane (5 mL) andacetic acid (1 mL). The mixture stirs at RT for 1 h and the resultingacid is purified via HPLC (method 1) to afford compound 127. LC/MS:[M+H₂O]⁺1361, R_(t)=1.27 min (method 13).

Example 113 Preparation of Acid (130)

Step 1:

To a solution alcohol 100 (190 mg, 0.160 mmol) in MeOH (11 mL) and DCM(11 mL) is added MnO₂ (696 mg, 8.0 mmol) which has been dried in highvacuum oven at 100° C. for 12 h. The mixture stirs 24 h. The mixture isthen adsorbed onto silica gel and purified by flash chromatography(gradient elution: 0-10% MeOH in DCM) which affords the aldehyde 128.LC/MS: [M+H]⁺ 1185, R_(t)=1.33 min (method 13).

Step 2:

To a solution of aldehyde 128 (72 mg, 0.061 mmol) in MeOH (1.5 mL) andDCM (1.5 mL) is added TEA (8 uL, 0.061 mmol), MgSO₄ (12 mg, 0.092 mmol),and 5-amino-pentanoic acid tert-butyl ester HCl (12 mL, 0.067 mmol, Syn.Commun. 2004, 34, 2415), is added. The mixture stirs 20 h. The mixtureis then cooled to 0° C. and NaBH₄ (14 mg, 0.366 mmol) is added. Themixture stirs 18 h at ambient temperature. Then additional NaBH₄ (14 mg,0.366 mmol) is added. The mixture stirs 1 h at ambient temperature. Themixture is then adsorbed onto silica gel and purified by flashchromatography (gradient elution: 0-50% MeOH/DCM+0.1% TEA) which affordsthe amine 129. LC/MS: [M+2H]⁺ 1343, R_(t)=1.24 min (method 13).

Step 3:

To the amine 129 is added 4 NCl in 1,4-dioxane (4 mL). The mixture stirsat RT for 0.5 h and the resulting acid is purified via HPLC (method 1)to afford the amino-acid 130. LC/MS: [M+H]⁺ 1286, R_(t)=1.06 min (method13).

Example 114 Preparation of Acid (133)

To a suspension of the acid (14, 392 mg, 0.326 mmol) in 11:1acetone:water (80.5 mL) is added triethylamine (0.45 mL, 3.26 mmol) andethyl chloroformate (0.37 mL, 3.91 mmol). The reaction is stirred atroom temperature until a solution forms (100 min.). Sodium azide (0.318g, 4.89 mmol) is added and the reaction is stirred at room temperatureuntil complete. Solvents are evaporated at 20° C. Water is added to theresidue to precipitate the azide. The azide is suspended three times inwater then once in dichloromethane and isolated by filtration. The azide131 is dried to a fine white powder. LC/MS: [M+H]⁺ 1298, R_(t)=1.47 min.(method 13).

Step 2:

The azide 131 (240.8 mg, 0.1854 mmol) is combined with4-hydroxy-cyclohexanecarboxylic acid methyl ester (88 mg, 0.556 mmol)and oven dried 3 angstrom molecular sieves (240.8 mg) in 1,4-dioxane (6mL) and stirred at 80° C. for 7 h. Solvent is evaporated and the residueis flashed on silica (gradient elution: 3-100% MeOH/DCM). The product isa pale yellow solid, 132. LC/MS: [M+2H]⁺ 1429, R_(t)=1.53 min (method13).

Step 3:

The ester 132 (100 mg, 0.700 mmol) is dissolved in 1:1dichloromethane:methanol (6 mL). 4N aqueous lithium hydroxide solution(0.3 mL, 1.2 mmol) is gradually added at room temperature with stirringover 7.25 hours. At 9.5 hours 0.5 mL of glacial acetic acid is added.Solvent is evaporated and the residue is purified by HPLC (20 to 100%acetonitrile in water+0.1% TFA) to afford compound 133. LC/MS: [M+H]⁺1342, R_(t)=1.26 min (method 13).

Example 115 Preparation of Acid (134)

Compound 134 is prepared according to the procedures in example 114.LC/MS: [M+H]⁺ 1236, R_(t)=1.17 min (method 13).

Example 116 Preparation of Amine (137)

Step 1:

To a mixture of pyrrolidine 13 (800 mg, 0.666 mmol) and DIPEA (1.16 ml,6.66 mmol) in DCM (64 mL) and MeOH (6 ml) is added TMSCHN₂ dropwise atRT under nitrogen. The reaction is stirred at RT for 2 h, kept at 0° C.for 48 h. The reaction is concentrated in vacuo, the residue is thenpoured onto H₂O (s), filtered to collect the solid, washed with coldwater, and dried in vacuo. The dried solid is treated with DCM andfiltered to give the methyl ether 135 as a white solid. LC/MS: [M+H]⁺1214, R_(t)=1.24 min (method 14).

Step 2:

To a solution of ether 135 (600 mg, 0.494 mmol) and pyridine (0.4 ml,4.94 mmol) in DMF (10 mL) is added Ac₂O (0.049 mL, 0.52 mmol) at 0° C.followed by DMAP (cat.). The reaction is stirred at RT at 0° C. for 7 h,and more Ac₂O (0.049 ml, 0.52 mmol) is added. The reaction is stirred atRT overnight. The mixture is poured onto ice and filtered, washed withcold water and dried in vacuum. The crude mixture is purified by flashchromatography (0-10% MeOH/DCM), and affords acetate 136 as a whitesolid. LC/MS: [M+H]⁺ 1256, R_(t)=1.31 min (method 14).

Step 3:

To a suspension of acetate 136 (50 mg, 0.04 mmol) and CDI (19.3 mg, 0.12mmol) in anhydrous DCM (2 mL) is added DMAP (5 mg, 0.04 mmol) at RT. Thereaction is stirred for 3 h and 1-(3-aminopropyl)-4-methylpiperazine(0.02 ml, 0.12 mmol) is added neat and stirred at RT for 3 h. The crudemixture is purified by HPLC (method 1) to afford 137. LC/MS: [M+H]⁺1439, R_(t)=0.41 min (method 14).

Example 117 Preparation of Amine (138)

Compound 138 is prepared according to the procedures described inexample 116. LC/MS: [M+H]⁺ 1370, R_(t)=0.46 min (method 13).

Example 118 Preparation of Amine (139)

Compound 139 is prepared according to the procedures described inexample 116. LC/MS: [M+H]⁺ 1415, R_(t)=0.81 min (method 13).

Example 119 Preparation of Amine (140)

Compound 140 is prepared according to the procedures described in scheme5 and example 34. LC/MS: [M+2H]⁺ 1438, R_(t)=1.05 min (method 13).

Example 120 Preparation of Amino-acid (141)

Compound 141 is prepared according to the procedures described in scheme5 and example 61. LC/MS: [M+H]⁺ 1466, R_(t)=1.03 min (method 14).

Example 121 Preparation of Amide (142)

Compound 142 is prepared according to the procedures described in scheme5. LC/MS: [M+H]⁺ 1632, R_(t)=1.22 min (method 13).

Example 122 Preparation of Amine (145)

Step 1:

To a solution of amide 13 (400 mg, 0.333 mmol) and pyridine (0.527 g,6.66 mmol) in DMF (40 mL) is added acetic anhydride (71.392 mg, 0.699mmol) at 0° C. under N₂, followed by DMAP (cat.). The solution isstirred at 0° C. overnight. Solvent is removed under vacuum. The residueis purified by flash chromatography (gradient elution: 0-10% MeOH/DCM)which affords the diacetate. LC/MS [M+2H]⁺ 1285, R_(t)=1.38 min (method13).

Step 2:

To a suspension of the diacetate (128 mg, 0.1 mmol) and CDI (48.5 mg,0.299 mmol) in anhydrous DCM is added DMAP (12.2 mg, 0.1 mmol) at RT andstirred for 3 h. When the starting material is consumed,N,N-dimethylethyldiamine is added, and the resulting reaction is stirredovernight. Solvent is removed under vacuum. The residue is purified viaHPLC (method 2) to furnish 144. LC/MS: [M+2H]⁺ 1357, R_(t)=1.14 min(method 13).

Step 3:

A suspension of compound 144 (40 mg, 0.0295 mmol) and potassiumcarbonate (12 mg, 0.0868 mmol) in DCM/MeOH (1 mL/1 mL) is stirred at RTfor 2 h. The reaction mixture is filtered to remove solid. The solventis removed under vacuum. The residue is purified via HPLC (method 1)which affords compound 145. LC/MS: [M+2H]⁺ 1315, R_(t)=1.10 min (method13).

Example 123 Preparation of Amine (146)

Compound 146 is prepared according to the procedures described inexample 122. LC/MS: [M+4H]⁺ 1428, R_(t)=0.40 min (method 13).

Example 124 Preparation of Amide (147)

Compound 147 is prepared according to the procedures described inexample 122. LC/MS: [M+2H]⁺ 1360, R_(t)=1.24 min (method 13).

Example 125 Preparation of Amine (148)

Compound 148 is prepared according to the procedures described inexample 122. LC/MS: [M+3H]⁺ 1342, R_(t)=1.10 min (method 13).

Example 126 Preparation of Amine (149)

Compound 149 is prepared according to the procedures described inexample 122. LC/MS: [M+2H]⁺ 1346, R_(t)=1.24 min (method 13).

Example 127 Preparation of Amine (150)

Compound 150 is prepared according to the procedures described inexample 122. LC/MS: [M+2H]⁺ 1329, R_(t)=1.05 min (method 13).

Example 128 Preparation of Imide (151)

Step 1:

A suspension of 144 (500 mg, 0.369 mmol) and potassium carbonate (153mg, 1.107 mmol) in DCM/MeOH (24 mL/24 mL) is stirred at 35° C. for 3 h.The solvent is removed under vacuum. Anhydrous DMSO (1-2 mL) is added tothe residue, and the resulting mixture is heated at 45° C. for 2 h.Water (15 mL) is added, and the reaction is stirred at RT. Theprecipitate is filtered, and washed with water. The solid is dried undervacuum to furnish the intermediate styrene. LC/MS: [M+2H]⁺1183,R_(t)=1.27 min (method 13).

Step 2:

To a mixture of the intermediate styrene (80 mg, 0.0677 mmol) in t-BuOH(2 mL) is added 0.1N HCl (1 mL), osmium tetroxide (2.5% wt in t-BuOH, 85uL, 0.00678 mmol), and a solution of sodium periodate (27 mg, 0.126mmol) in H₂O (2 mL). The resulting reaction mixture is stirred 12 h atRT. Water (6 mL) is added, and the precipitate is filtered andcollected. The solid is redissolved in DMF/MeCN, purified with HPLC(method 1) and further purified by flash chromatography (gradientelution: 0-10% MeOH/DCM) which provides compound 151. LC/MS: [M+2H]⁺1109, R_(t)=1.17 min (method 13).

Example 129 Preparation of Acid (155)

Step 1:

To a solution of amide 34 (960 mg, 0.72 mmol) in DMF (5 mL) is addedtert-butylbromoacetate (221 uL, 1.51 mmol) and K₂CO₃(248 mg, 1.79 mmol).The reaction stirs at RT for overnight. When LC-MS indicates thatreaction is finished, 50 mL water is added to the mixture to precipitateproduct. The mixture is then filtered and washed with water twice toremove K₂CO₃ and DMF. Compound 152 is obtained and dried for 12 h invacuum oven (1.04 g). LC/MS: [M+2H]⁺ 1455, R_(t)=1.56 min (method 10).

Step 2:

To a solution of tert-butyl ester 152 (1.04 g, 0.72 mmol) in DCM (20 mL)is added TFA (2.7 mL, 36 mmol). The reaction stirs at RT for 5 h and ismounted onto SiO₂ and purified by flash chromatography (10% MeOH/DCM)which results in the recovery of 472 mg of acid 153. The impurefractions are combined and purified by RP-HPLC (20-90% ACN/0.015 Mammonium hydroxide in water) which results in the recovery of another232 mg of acid 153. LC/MS: [M+2H]⁺ 1399, R_(t)=1.29 min (method 10).

Step 3:

To a solution of acid 153 (135 mg, 0.097 mmol) in DMF (20 mL) is addedDIPEA (51 uL, 0.291 mmol), methoxypolyethylene glycol amine 750 (146 mg,0.194 mmol, n(average)=15.2) and HATU (92 mg, 0.24 mmol). The reactionstirs at RT for 1 h and is quenched by adding water. The aqueous phaseis extracted with 5% MeOH/DCM three times, combined organic phases isdried over sodium sulfate, filtered, concentrated in vacuo and purifiedby flash chromatography (10% MeOH/DCM) which results in the recovery of230.5 mg of ester 154. LC/MS: [M+2H⁺ H₂O]⁺1068 (n=15), R_(t)=1.34 min(method 10).

Step 4:

To a solution of ester 154 (230.5 mg, 0.108 mmol) in THF (2 mL) is addedLiOH (2.7 mL, 0.1 M). The reaction stirs at RT for 5 h and is quenchedby adding 1 N HCl (0.26 mL). The mixture is concentrated in vacuo andpurified by HPLC (10-60% ACN/0.015 M ammonium hydroxide in water)affords 155. LC/MS: [M+2H⁺ H₂O]⁺1061 (when n=15), R_(t)=1.17 min (method10).

Example 130 Preparation of Diacid (156)

Compound 156 is prepared as described in scheme 13 and in example 129.LC/MS: [M+3H]⁺ 1386, R_(t), 1.06 min (method 10).

Example 131 Preparation of Amino-acid (157)

Compound 157 is prepared as described in scheme 13 and in example 129.LC/MS: [M/2+2H]⁺ 742, R_(t) 1.06 min (method 10).

Example 132 Preparation of Acid (158)

Compound 158 is prepared as described in scheme 13 and in example 129.LC/MS: [M+2H]⁺ 1496, R_(t), 1.25 min (method 10).

Example 133 Preparation of Amino-acid (159)

Compound 159 is prepared as described in scheme 13 and in example 129.LC/MS: [M+2H]⁺ 1467, R_(t), 1.09 min (method 10).

Example 134 Preparation of Acid (160)

Compound 160 is prepared as described in scheme 13 and in example 129.LC/MS: [M+2H]⁺ 1496, R_(t), 1.10 min (method 10).

Example 135 Preparation of Diacid (161)

Compound 161 is prepared as described in scheme 13 and in example 129.LC/MS: [M+3H]⁺ 1499, R_(t), 1.12 min (method 10).

Example 136 Preparation of Acid (162)

Compound 162 is prepared as described in scheme 13 and in example 129.LC/MS: [M/2+2H]⁺ 729, R_(t), 1.21 min (method 10).

Example 137 Preparation of Acid (163)

Compound 163 is prepared as described in scheme 13 and in example 129.LC/MS: [M+2H]⁺ 1350, R_(t), 1.13 min (method 10).

Example 138 Preparation of Diacid (164)

Compound 164 is prepared as described in scheme 5. LC/MS: [M+H]⁺ 1224,R_(t)=1.04 min (method 10).

Example 139 Preparation of Diacid (167)

Step 1:

To a solution of compound 132 (scheme 10, 680 mg) in dichloromethane (57mL) are added triethylamine (0.6 mL), acetic anhydride (0.44 mL) and4-di(methylamino)pyridine (57 mg) at 20° C. The reaction is stirred atroom temperature for 1 hour. The solvents are evaporated and the residueis flashed on silica (gradient elution 0-10% i—PrOH/DCM) to afford 600mg of the diacetate 165. LC/MS: [M+H₃O]⁺1531, R_(t)=1.65 min (method13).

Step 2:

To a solution of the diacetate (165) (600 mg in 18 mLN,N-dimethylformamide) are added oven dried 4 angstrom molecular sieves(1.15 g), methyl-5-bromovalerate (1.13 mL) and cesium carbonate (1.29g). The reaction is stirred at room temperature until complete. Aceticacid (5 mL) and silica (6 g) are added and the mixture is evaporated todryness. Flash chromatography (gradient elution: 0-10% i—PrOH/DCM)provides 522 mg yellow solid 166. LC/MS: [M+H]⁺ 1627, R_(t)=1.74 min(method 14).

Step 3:

Compound 166 (505 mg) is dissolved in 1:1 dichloromethane:methanol (30mL) and chilled to 0° C. Saturated lithium hydroxide solution (5 mL) isadded slowly. The reaction is stirred at 0° C. until complete, thenquenched with 10 mL acetic acid. The solvent is evaporated and theresidue purified by HPLC to produce compound 167, 240 mg. LC/MS: [M+2H]⁺1443, R_(t)=1.39 min (method 9).

Example 140 Preparation of Amine (170, 171)

Step 1:

A mixture of 13 (2 g, 1.667 mmol), TBDMSTFA(N-tert-butyldimethylsilyl-N-methyltrifluoroacetamide, 2.642 g, 10.948mmol) and DMF/DCM (10 mL/20 mL) is stirred at RT for 4 h. The solvent isremoved under reduced pressure at 40° C. The residue is purified byflash chromatography (gradient elution: 0-10% MeOH/DCM) which affords 1g of 168. LC/MS: [M+2H]⁺ 1315, R_(t)=1.56 min (method 13).

Step 2:

To a suspension of 168 (560 mg, 0.426 mmol) and potassium carbonate (924mg, 6.686 mmol) in anhydrous DMF (10 ml) is added t-butyl bromoacetate(1.305 g, 6.690 mmol). The resulting reaction is stirred at RT under N₂overnight. The solid is filtered, and the solvent is removed underreduced vacuum. The residue is purified by flash chromatography(gradient elution: 1-6% MeOH/DCM) which affords 250 mg of 169. LC/MS:[M+4H]⁺ 1431, R_(t)=1.75 min (method 13).

Step 3:

A solution of 169 (500 mg, 0.350 mmol), TFA (3.5 mL) and thioanisole (2mL) in DCM (12 mL) is stirred at RT overnight. Additional TFA is addeduntil the starting material disappears. The solvent is removed underreduced vacuum, and the residue is purified by flash chromatography(gradient elution: 5-20% MeOH/DCM) which affords 240 mg of 170. LC/MS:[M+3H]⁺ 1260, R_(t) 1.14 min (method 13).

Step 4:

A solution of 170 (50 mg, 0.0397 mmol), N,N-dimethylethyldiamine (3.50mg, 0.0397 mmol), HATU (20 mg, 0.0526 mmol), DIPEA (51.213 mg, 0.397mmol) in DMF (1 mL) is stirred at RT overnight. The solvent is removedunder reduced pressure. The residue is purified by flash chromatography(gradient elution: 10-20% MeOH/DCM) which affords 15 mg of 171. LC/MS:[M+2H]⁺ 1329, R_(t), 1.06 min (method 13).

Example 141 Preparation of Amine (172)

Compound 172 is prepared according to the procedures described inexample 140. LC/MS: [M+2H]⁺ 1371, R_(t)=1.17 min (method 13).

Example 142 Preparation of Acid (173)

Compound 173 is prepared according to the procedures described inexample 140. LC/MS: [M+2H]⁺ 1330, R_(t)=1.13 min (method 13).

Example 143 Preparation of Diacid (174)

Compound 174 is prepared according to the procedures described inexample 139. LC/MS: [M+H]⁺ 1388, R_(t)=1.27 min (method 14).

BIOLOGICAL ACTIVITY

Using standard MIC test described above with the bacteria Enterococcusfaecalis, Enterococcus faecium, Staphylococcus aureus, or Streptomycespyogenes, compounds 1-17, 20-24, 26, 29-37, 39, 40, 42-66, 69-98,100-115, 117-124, 127, 130, 133, 134, 137-142, 145-151, 155-164, 167,170-174 demonstrate a minimum inhibitory concentration of <32 mg/mL.

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments and methods described herein. Such equivalents are intendedto be encompassed by the scope of the following claims.

The invention claimed is:
 1. A compound of Formula III:

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including pyridine N-oxides thereof; wherein q is 1, or 2 and thefragment

is selected from the group consisting of:

q is 0 and E-R₁ is selected from the group consisting of:

R₁ is selected from the group consisting of hydrogen, hydroxymethyl, andaminomethyl and R₁₂: R_(2a) is hydrogen, hydroxy or amino, or isselected from the group consisting of C₁₋₈alkoxy, amino, mono- anddi-C₁₋₈alkylamino, C₃₋₇cycloalkylC₀₋₆alkoxy, each of which issubstituted with hydroxy, oxo, halo, C₁₋₈alkyl, haloC₁₋₈alkyl,C₁₋₈alkoxy, haloC₁₋₈alkoxy, C₃₋₇cycloalkylC₀₋₆alkyl, COOH, NH₂, mono-and di-C₁₋₈alkylamino, tri-C₁₋₈alkylammonium, heterocycleC₀₋₆alkyl,heteroarylC₀₋₆alkyl, or —(CH₂—CH₂—O—)_(n)—R₈; R₃ is selected from R₁₂,OR₁₂, N(R₁₂)₂ or R₁₃; R₄ is selected from hydrogen, CO₂R_(4a),C(O)N(R_(4a))₂, OR_(3a), N(R_(3a))₂, or C(R₁₀)(R₁₁)phenyl; R_(4a) isindependently selected at each occurrence from hydrogen, hydroxymethyl,aminomethyl or R₁₂; R₆ is hydrogen or C₁₋₄alkyl; R₇ is selected from thegroup consisting of H, OH, NH₂, C₁₋₈alkyl, C₁₋₈alkoxy, and mono- anddi-C₁₋₈alkylamino; R_(7b) is independently selected at each occurrencefrom the group consisting of H, C₁₋₈alkyl and —(CH₂—CH₂—O—)_(n)—R₈; R₈is independently selected at each occurrence from the group consistingof H, C₁₋₈alkyl and CH₂CO₂H; R₁₀ is absent or hydrogen; R₁₁ is oxo,OR_(4a), N(R_(4a))₂, or ═NR_(4a); R₁₂ is independently selected at eachoccurrence from the group consisting of

R₁₃ is independently selected from the group consisting of

n is an integer of between 1-60,000 or is a mean of a plurality ofintegers having a value of between 1-60,000; and p is 0, 1, 2, 3, or 4.2. The compound of claim 1, wherein R₇ and each occurrence of R_(7b) arehydrogen.
 3. The compound of claim 1, wherein q is 0; E-R₁ is selectedfrom the group consisting of

R₁ and R₉ are independently selected from the group consisting ofhydrogen, hydroxymethyl, aminomethyl and R₁₂; R₁₂ is independentlyselected at each occurrence from the group consisting of:

and pharmaceutically acceptable salts thereof.
 4. The compound of claim1, wherein R_(2a) is selected from hydrogen, amino, hydroxy, halogen, oris selected from the group consisting of

p is 0, 1, 2, 3, or
 4. 5. The compound of claim 1, wherein R₃ isselected from R_(3a), OR_(3a) or N(R_(3a))₂; or R₃ is selected from thegroup consisting of

p is 0, 1, 2, 3, or 4; and R_(3a) is independently selected, at eachoccurrence from hydrogen , hydroxymethyl, and aminomethyl or from thegroup consisting of:

and pharmaceutically acceptable salts thereof.
 6. The compound of claim1, wherein R₄ is selected from hydrogen, CO₂R_(4a), C(O)N(R_(4a))₂,N(R_(4a))₂, or C(R₁₀)(R₁₁)phenyl; R₁₀ is absent or hydrogen; R₁₁ is oxo,OR_(4a), C(O)R_(4a), C(O)OR_(4a), C(O)N(R_(4a))₂, OC(O)N(R_(4a))₂,N(R_(4a))₂, or ═NR_(4a); R_(4a) is independently selected at eachoccurrence from hydrogen, hydroxymethyl, and aminomethyl or from thegroup consisting of:

and pharmaceutically acceptable salts thereof.
 7. A compound of FormulaIV

and pharmaceutically acceptable salts, enantiomers, stereoisomers,rotamers, tautomers, diastereomers, atropisomers or racemates thereof,including pyridine N-oxides thereof; wherein E is selected from thegroup consisting of C(O), C(O)C(O), C(O)O, N(R₉), C(O)N(R₉), N(R₉)C(O),N(R₉)C(O)C(O), N(R₉)C(O)O, N(R₉)C(O)N(R₉), S(O)₂, S(O)₂N(R₉),N(R₉)S(O)₂, and N(R₉)S(O)₂N(R₉); R₁ is hydrogen or is selected from thegroup consisting of C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, C₁-₈alkoxy,cycloalkylC₀₋₆alkyl, heterocycloalkylC₀₋₆alkyl, arylC₀₋₆alkyl,heteroarylC₀₋₆alkyl each of which is substituted with 0 to 6 residuesindependently selected at each occurrence from the group consisting ofhydroxy, oxo, C₁₋₈alkyl, C₁₋₈alkoxy, C₃₋₇cycloalkylC₀₋₆alkyl, COOH, NH₂,mono- and di-C₁₋₈alkylamino, tri-C₁₋₈alkylammonium,heterocycleC₀₋₆alkyl, heteroarylC₀₋₆alkyl and —(CH₂—CH₂—O—)_(n)—R₈; R₈is independently selected at each occurrence from the group consistingof H, C₁₋₈alkyl and CH₂CO₂H; and R₉ is hydrogen or is selected from thegroup consisting of C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, C₁-₈alkoxy,cycloalkylC₀₋₆alkyl, heterocycloalkylC₀₋₆alkyl, arylC₀₋₆alkyl,heteroarylC₀₋₆alkyl each of which is substituted with 0 to 6 residuesindependently selected at each occurrence from the group consisting ofhydroxy, oxo, C₁₋₈alkyl, C₁₋₈alkoxy, C₃₋₇cycloalkylC₀₋₆alkyl, COOH, NH₂,mono- and di-C₁₋₈alkylamino, tri-C₁₋₈alkylammonium,heterocycleC₀₋₆alkyl, heteroarylC₀₋₆alkyl and —(CH₂—CH₂—O—)_(n)—R₈. 8.The compound of claim 7, wherein R₁ and R₉ are independently selected ateach occurrence from the group consisting of H, C₁₋₈alkyl,C₃₋₈cycloalkyl, and R₁₂, wherein the C₁-₈alkyl and C₃₋₈cycloalkyl groupsare unsubstituted or substituted with 1 or 2 groups selected fromhalogen, hydroxyl, or COOH; R₁₂ is independently selected at eachoccurrence from the group consisting of

n is an integer of between 1-60,000 or is a mean of a plurality ofintegers having a value of between 1-60,000.
 9. The compound of claim 8,wherein E-R₁ is selected from the group consisting of

and R₁ and R₉ are independently selected from the group consisting ofhydrogen, hydroxymethyl, aminomethyl and R₁₂; and pharmaceuticallyacceptable salts thereof.
 10. A compound selected from the groupconsisting of:


11. A pharmaceutical composition, comprising: the compound of claim 1,and at least one pharmaceutically acceptable carrier or diluent.
 12. Apharmaceutical composition, comprising: the compound of claim 7, and atleast one pharmaceutically acceptable carrier or diluent.